Abstract:

The invention is concerned with novel heterocyclyl compounds of formula
(I):
##STR00001##
wherein A, X, R3, R4, R5, R6, R7, R8,
R9, R10, m, n and p are as defined in the description and in
the claims, as well as physiologically acceptable salts thereof. These
compounds are antagonists of CCR2 receptor, CCR5 receptor and/or CCR3
receptor and may be used as medicaments.

Claims:

1. A compound of formula (I): ##STR00122## or a pharmaceutically
acceptable salt or ester thereof, wherein:A is aryl, heteroaryl,
arylmethyl or heteroarylmethyl, wherein said aryl or heteroaryl portion
of A is optionally substituted by one to three substituents independently
selected from the group consisting of halogen, aryl, heteroaryl,
C1-6 alkyl, halo C1-6 alkyl, C1-6 alkoxy, halo C1-6
alkoxy, and C1-6 alkylenedioxy;X is --N(R1)(R1);R1
and R2 are independently selected from the group consisting of:(1)
hydrogen,(2) C1-6 alkyl,(3) C3-6 alkenyl,(4) C3-6
alkynyl,(5) hydroxy C2-6 alkyl,(6) C1-6 alkoxy C2-6
alkyl,(7) C3-7 cycloalkyl, which is optionally substituted one to
three times by Rd,(8) C3-7 cycloalkyl C1-6 alkyl, wherein
the C3-7 cycloalkyl portion of said C3-7 cycloalkyl C1-6
alkyl is optionally substituted one to three times by Rd,(9)
C7-10 bicycloalkyl,(10) phenyl C1-3 alkyl, wherein the phenyl
portion of said phenyl C1-3 alkyl is optionally substituted one to
three times by Rd,(11) heteroaryl C1-3 alkyl, wherein the
heteroaryl portion of said heteroaryl C1-3 alkyl is optionally
substituted one to three times by Rd,(12) heterocyclyl, which is
optionally substituted one to three times by Rd, and(13)
heterocyclyl C1-6 alkyl, wherein the heterocyclyl portion of said
heterocyclyl C1-6 alkyl is optionally substituted one to three times
by Rd;provided that at least one of R1 and R2 is not
hydrogen; or alternatively,R1 and R2, together with the
nitrogen atom to which they are attached, form a heterocyclyl optionally
substituted one to three times by Rd, and wherein: (a) one of the
ring carbon atoms of said heterocyclyl formed by R1 and R2 is
optionally replaced with a carbonyl group; and/or (b) one of the ring
carbon atoms of said heterocyclyl formed by R1 and R2 is also a
ring carbon atom of another ring which is a C3-7 cycloalkyl or
heterocyclyl, which is optionally substituted by a C1-6 alkyl, and
wherein one or two ring carbon atoms of said C3-7 cycloalkyl or
heterocyclyl is optionally replaced by a carbonyl group;R3 and
R4 are independently selected from the group consisting of:(1)
hydrogen,(2) hydroxy,(3) C1-6 alkyl,(4) C1-6 alkoxy,(5)
C3-7 cycloalkyl,(6) C3-7 cycloalkyl C1-6 alkyl,(7)
C1-6 alkoxycarbonyl,(8) carboxyl,(9) carbamoyl,(10) mono or
di-C1-6 alkyl substituted carbamoyl,(11) C1-6
alkoxycarbonyloxy,(12) mono or di-C1-6 alkyl substituted
aminocarbonyloxy,(13) hydroxy-C1-6 alkyl,(14) C1-6
alkoxy-C1-6 alkyl,(15) halogen or halo C1-6 alkyl,(16)
optionally substituted heterocyclyl-carbonyl, and(17)
RaaRbbN--C(O)-- wherein Raa and Rbb are independently
selected from the group consisting of hydrogen, C1-6 alkyl,
hydroxy-C1-6 alkyl and C3-7 cycloalkyl; or
alternatively,R3 and R4, together with the carbon atom to which
they are attached, form C3-7 cycloalkyl or heterocyclyl optionally
substituted by one to three substituents independently selected from the
group consisting of C1-4 alkyl, halo C1-4 alkyl and
halogen;R5 and R6 are independently hydrogen, C1-6 alkyl
or C3-7 cycloalkyl, wherein said C1-6 alkyl and said C3-7
cycloalkyl are optionally substituted by one to three substituents
independently selected from the group consisting of: (1) amino, (2)
hydroxy, (3) carboxyl, (4) carbamoyl, (5) mono or di-C1-6 alkyl
substituted carbamoyl and (6) C1-6 alkoxycarbonyl; or alternatively
R5 and R6, together with the carbon atom to which they are
attached, form C3-7 cycloalkyl or heterocyclyl;R7, R8,
R9 and R10 are independently hydrogen, C1-6 alkyl,
C3-7 cycloalkyl, or aryl; wherein said C1-6 alkyl is optionally
substituted by one to three substituents independently selected from the
group consisting of:(1) hydroxy,(2) C1-6 alkoxy,(3) carboxyl,(4)
carbamoyl,(5) mono or di-C1-6 alkyl substituted carbamoyl,(6)
C1-6 alkoxycarbonyl,(7) aryl, optionally substituted by one to three
substituents independently selected from the group consisting of halogen,
C1-6 alkyl, halo C1-6 alkyl, C1-6 alkoxy and halo
C1-6 alkoxy, and(8) heteroaryl, optionally substituted by one to
three substituents independently selected from the group consisting of
halogen, C1-6 alkyl, halo C1-6 alkyl, C1-6 alkoxy and halo
C1-6 alkoxy;Rd is selected from the group consisting of:(1)
hydroxy,(2) cyano,(3) NRaRb,(4) halogen,(5) C1-6 alkyl,(6)
halo C1-6 alkyl,(7) hydroxy C1-6 alkyl,(8) C1-6 alkoxy,(9)
C1-6 alkoxy C1-6 alkyl,(10) C3-7 cycloalkyl,(11) C1-6
alkoxycarbonyl,(12) acyl,(13) --C(O)NRaRb,(14)
--NRa--C(O)--Rb,(15) --NRa--C(O)--ORb,(16)
--NRa--C(O)--NRb,(17) --NRa--SO2--Rb,(18)
--NRa--SO2--NRbRc,(19) --OC(O)NRaRb,(20)
--OC(O)ORa,(21) C1-6 alkylsulfonyl,(22) C1-6
alkylsulfinyl,(23) C1-6 alkylthio,(24) phenyl or phenyl C1-3
alkyl, wherein the phenyl or phenyl portion of said phenyl C1-3
alkyl is optionally substituted one to three times by a substituent
independently selected from the group consisting of hydroxy, cyano,
NRaRb, halogen, C1-6 alkyl, halo C1-6 alkyl, hydroxy
C1-6 alkyl, C1-6 alkoxycarbonyl, acyl, --C(O)NRaRb,
--NRa--C(O)--Rb, --NRa--C(O)ORb,
--NRa--C(O)--NRb, --NRa--SO2--Rb,
--NRa--SO2--NRbRc, --OC(O)NRaRb,
--OC(O)ORa, C1-6 alkylsulfonyl, C1-6 alkylsulfinyl, and
C1-6 alkylthio;(25) heteroaryl or heteroaryl C1-3 alkyl,
wherein the heteroaryl or heteroaryl portion of said heteroaryl C1-3
alkyl is optionally substituted one to three times by a substituent
independently selected from the group consisting of hydroxy, cyano,
NRaRb, halogen, C1-6 alkyl, halo C1-6 alkyl, hydroxy
C1-6 alkyl, C1-6 alkoxycarbonyl, acyl, --C(O)NRaRb,
--NRaC(O)--Rb, --NRa--C(O)--ORb,
--NRa--C(O)--NRb, --NRa--SO2--Rb,
--NRaSO2--NRbRc, --OC(O)NRaRb,
--OC(O)ORa, C1-6 alkylsulfonyl, C1-6 alkylsulfinyl, and
C1-6 alkylthio; and(26) heterocyclyl, which is optionally
substituted one to three times by a substituent independently selected
from the group consisting of hydroxy, cyano, NRaRb, halogen,
C1-6 alkyl, halo C1-6 alkyl, hydroxy C1-6 alkyl, C1-6
alkoxycarbonyl, acyl, --C(O)NRaRb, --NRa--C(O)--Rb,
--NRa--C(O)--ORb, --NRaC(O)--NRb,
--NRa--SO2--Rb, --NRa--SO2--NRbRc,
--OC(O)NRaRb, --OC(O)ORa, C1-6 alkylsulfonyl,
C1-6 alkylsulfinyl, and C1-6 alkylthio, and wherein one or two
ring carbon atoms of the heterocyclyl is optionally replaced with a
carbonyl group;Ra, Rb and Rc are independently hydrogen or
C1-6 alkyl;m is an integer of 0 to 3; n is an integer of 0 to 3; m+n
is an integer of 1 to 5; andp is 0 or 1.

2. A compound of according to claim 1, wherein R3 and R4 are
independently selected from the group consisting of:(1) hydrogen,(2)
hydroxy,(3) C1-6 alkyl,(4) C1-6 alkoxy,(5) C3-7
cycloalkyl,(6) C3-7 cycloalkyl C1-6 alkyl,(7) C1-6
alkoxycarbonyl,(8) carboxyl,(9) carbamoyl,(10) mono or di-C1-6 alkyl
substituted carbamoyl,(11) C1-6 alkoxycarbonyloxy,(12) mono or
di-C1-6 alkyl substituted aminocarbonyloxy,(13) hydroxy-C1-6
alkyl,(14) C1-6 alkoxy-C1-6 alkyl, and(15) halogen or halo
C1-6 alkyl, or alternatively,R3 and R4, together with the
carbon atom to which they are attached, form C3-7 cycloalkyl or
heterocyclyl optionally substituted by one to three substituents
independently selected from the group consisting of C1-4 alkyl, halo
C1-4 alkyl and halogen;

3. A compound according to claim 1, wherein A is phenyl or naphthyl, which
is optionally substituted by one to three substituents independently
selected from the group consisting of halogen, halo C1-6 alkyl, halo
C1-6 alkoxy and aryl.

4. A compound according to claim 1, wherein A is phenyl substituted by one
or two substituents independently selected from the group consisting of
halogen, halo C1-6 alkyl and halo C1-6 alkoxy.

5. A compound according to claim 1, wherein A is phenyl substituted by one
or two substituents independently selected from the group consisting of
chloro, trifluoromethyl, and trifluoromethoxy.

6. A compound according to claim 1, wherein A is 3,4-dichlorophenyl,
3-chlorophenyl, 3-trifluoromethylphenyl, 3-Chloro-4trifluoromethylphenyl,
or 3-trifluoromethoxylphenyl.

7. A compound according to claim 1, wherein X is --N(R1)(R2) and
R1 and R2, together with the nitrogen atom to which they are
attached, form heterocyclyl optionally substituted by one to three
substituents independently selected from the group consisting of hydroxy,
C1-6 alkyl and hydroxy C1-6 alkyl; and one of the ring carbon
atoms of the heterocyclyl formed by R1 and R2 may also be a
ring carbon atom of another ring which is a C3-7 cycloalkyl.

8. A compound according to claim 1, wherein X is a mono
spiro-heterocyclyl, wherein the spiro-heterocyclyl ring is optionally
substituted by one to three substituents independently selected from the
group consisting of hydroxy, oxo, alkoxy, fluoro, and C1-6 alkyl.

9. A compound according to claim 1, wherein X is -aza-spiro[2,5]oct-6-yl,
5-azaspiro[2.5]oct-5-yl, 7-aza-spiro[3.5]non-7-yl,
8-aza-spiro[4.5]dec-8-yl, 1,8diaza-spiro[4.5]dec-8-yl,
1,3,8-triaza-spiro[4.5]dec-8-yl, 2,8-diaza-spiro[4.5]dec-8-yl,
1-oxa-3,8-diaza-spiro[4.5]dec-8-yl, 1-oxa-8-aza-spiro[4.5]dec-8-yl,
2-oxa-8-aza-spiro[4.5]dec-8-yl, 2-oxa-7-aza-spiro[3.5]non-7-yl,
1-oxa-7-aza-spiro[3.5]non-7-yl, 9-aza-spiro[5.5]undec-9-yl, or
1-oxa-4,9-diaza-spiro[5.5]undec-9-yl, wherein the spiro-heterocyclyl ring
is optionally substituted by one to three substituents independently
selected from the group consisting of hydroxy, oxo, alkoxy, fluoro, and
C1-6 alkyl.

10. A compound according to claim 1, wherein the heterocyclyl formed by
R1 and R2, together with the nitrogen atom to which they are
attached, is piperidyl or pyrrolidinyl, and said piperidyl or
pyrrolidinyl is optionally substituted by one or two substituents
independently selected from the group consisting of hydroxy, C1-6
alkyl, and hydroxy C1-6 alkyl; and wherein one of the ring carbon
atoms of said piperidyl or pyrrolidinyl is optionally shared by a
cyclopropyl ring.

11. A compound according to claim 1, wherein X is
(S)-4-Hydroxy-6-aza-spiro[2.5]oct-6-yl.

12. A compound according to claim 1, wherein m+n is an integer of 1, 2 or
3.

14. A compound according to claim 1, wherein n is 0, m is 2 and one of
R3 and R4 is hydrogen, and the other is selected from the group
consisting of hydrogen, C1-6 alkoxycarbonyl, hydroxy-C1-6
alkyl, C1-6 alkoxy-C1-6 alkyl, carboxyl, and mono or
di-C1-6 alkyl substituted carbamoyl.

15. A compound according to claim 1, wherein one or two of R5,
R6, R7, R8, R9 and R10 are independently
hydrogen, C1-6 alkyl, phenyl, and phenyl-C1-6 alkyl optionally
substituted by trifluoromethyl; and the others are hydrogen.

16. A compound according to claim 1, wherein one of R5 and R6 is
hydrogen or C1-6 alkyl, and the other is hydrogen; one of R9
and R10 is hydrogen or C1-6 alkyl, and the other is hydrogen;
and R7 and R8 are hydrogen.

17. A compound according to claim 1, wherein one of R5 and R6 is
hydrogen or C1-6 alkyl, and the other is hydrogen; one of R9
and R10 is hydrogen or methyl, and the other is hydrogen, and
R7 and R8 are hydrogen.

18. A compound according to claim 1, wherein one of R5 and R6 is
hydrogen or C1-6 alkyl, and the other is hydrogen; and R7,
R8, R9 and R10 are hydrogen.

19. A compound according to claim 1, wherein one of R5 and R6 is
methyl, and the other is hydrogen; and R7, R8, R9 and
R10 are hydrogen.

23. A process for manufacturing a compound of formula (I): ##STR00128##
comprising a step of reacting a compound of formula 9: ##STR00129## with
A-LG2, A-B(OH)2 or A'-CHO,wherein A, X, R3, R4,
R5, R6, R7, R8, R9, R10, m, n and p are as
defined in claim 1, A' is aryl or heteroaryl, and LG2 is a leaving
group.

24. A pharmaceutical composition comprising a compound of claim 1 and a
pharmaceutically acceptable excipient.

Description:

PRIORITY TO RELATED APPLICATION(S)

[0001]This application claims the benefit of European Patent Application
No. 08161278.0, filed Jul. 28, 2008, which is hereby incorporated by
reference in its entirety.

BACKGROUND OF THE INVENTION

[0002]Chemokines are a family of small, secreted proinflammatory cytokines
functioning as chemoattractants for leukocytes. They promote trafficking
of leukocytes from vascular beds into surrounding tissues in response to
inflammatory signals. Chemotaxis starts upon chemokine binding to
receptors (GPCRs) by initiating signaling pathways involving increased
Ca-flux, inhibition of cAMP production, rearrangements of the
cytoskeleton, activation of integrins and of cell motility processes and
an increase in the expression of adhesion proteins.

[0003]Proinflammatory chemokines are considered to be involved in the
development of atherosclerosis and other important diseases with
inflammatory components like rheumatoid arthritis, asthma, multiple
sclerosis, transplant rejection and ischemia reperfusion injury with
specific prominent effects in nephropathy and peripheral vascular
diseases. Monocyte Chemotactic protein 1 is considered to be the major
stimulated chemokine mediating inflammatory processes in these diseases
through the CCR2 receptor on monocytes and on some T lymphocytes. In
addition MCP-1/CCR2 are in discussion to be related to the progression of
the metabolic syndrome to more severe stages of obese and diabetic
diseases. CCR2 has also been linked to HIV infection, and consequently
the course of autoimmune diseases, through its heterodimerization with
CCR5 which has a role as coreceptor for viral entry into host cells.

[0004]Thus, CCR2 can be a target of a new medicine for treatment of
peripheral vascular diseases, and more specifically for treatment of
patients with critical limb ischemia. Furthermore, study results and
experiences from the development of a new CCR2 medicine for this
indication may facilitate a follow-up development for treatment of
atherosclerosis. There is a large body of information from animal models
of MCP-1 and CCR2 ko mice in wt or apoE-/- or LDL-R-/- backgrounds
showing that the MCP-1/CCR2 pathway is essential for monocyte/macrophage
recruitment, and also for intimal hyperplasia and the formation and
stability of atherosclerotic lesions. In addition, numerous reports
describe involvement of the MCP-1/CCR2 pathway in man post injury and in
various inflammatory processes, including such in vascular beds.

and pharmaceutically acceptable salts, prodrugs, or esters thereof,
wherein A, X, R3-R10, n, m, and p are as defined in the
detailed description and claims.

[0006]The compounds of formula (I) are CCR2 receptor (Chemokine Receptor
2/Monocyte chemotactic protein 1 receptor) antagonists and also CCR5
receptor (Chemokine Receptor 5) and/or CCR3 receptor (Chemokine Receptor
3) antagonists which may be useful in the treatment of diseases or
disorders associated with such receptors. Further, the invention is
concerned with a process and an intermediate for the manufacture of such
compounds and pharmaceutical compositions which contain such compounds.

DETAILED DESCRIPTION OF THE INVENTION

[0007]Unless otherwise indicated, the following definitions are set forth
to illustrate and define the meaning and scope of the various terms used
to describe the invention herein.

[0008]The term "hydrogen" or "hydro" refers to the moiety of a hydrogen
atom (--H) and not H2.

[0010]The term "C1-6 alkyl," alone or in combination with other
groups, means a branched or straight-chain monovalent alkyl radical,
having one to six carbon atoms. This term is further exemplified by such
radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl,
t-butyl. C1-4 alkyl or C1-3 alkyl is more preferred. The term
"C2-6 alkyl" means the same as a "C1-6 alkyl", except that the
C2-6 alkyl has two to six carbon atoms.

[0011]The term "hydroxy C1-6 alkyl" means a C1-6 alkyl
substituted by one or more hydroxy group(s).

[0012]The term "halo C1-6 alkyl" means a C1-6 alkyl substituted
by one or more of the same or different halogen atoms. Examples are
1-fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl,
2-fluoroethyl and 2,2,2-trifluoroethyl. The most preferred "halo
C1-6 alkyl" is trifluoromethyl.

[0013]The term "C3-7 cycloalkyl," alone or in combination with other
groups, means a saturated monovalent mono-cyclic hydrocarbon radical of
three to seven ring carbons (e.g., cyclopropyl, cyclobutyl, or
cyclohexyl).

[0014]The term "C3-7 cycloalkyl C1-6 alkyl" means a C1-6
alkyl substituted by one or more C3-7 cycloalkyl groups, as defined
herein.

[0015]The term "C7-10 bicycloalkyl," alone or in combination with
other groups, means a saturated monovalent cyclic hydrocarbon radical of
seven to ten ring carbons, having two rings, in which two or more ring
carbon atoms of one ring are ring carbon atoms of the other ring (e.g.,
bicyclo[2.2.1]heptyl).

[0016]The term "C1-6 alkoxy," alone or in combination with other
groups, means the group R'--O--, wherein R' is a C1-6 alkyl.

[0017]The term "C1-6 alkoxy-carbonyl" refers to the group
Ra1--C(O)--, wherein Ra1 is a C1-6 alkoxy as defined
above.

[0019]The term "halo C1-6 alkoxy," alone or in combination with other
groups, means a C1-6 alkoxy substituted by one or more halogens. In
particular embodiments the C1-6 alkoxy is substituted by one to
three halogens.

[0020]The term "C1-6 alkylenedioxy" means --O--C1-6 alkyl-O--.
When a group is substituted by a C1-6 alkylenedioxy, each end of the
C1-6 alkylenedioxy replaces a hydrogen atom of that group.
Methylenedioxy or 1,2-ethylenedioxy are preferred examples.

[0021]The term "C3-6 alkenyl," alone or in combination with other
groups, means a straight-chain or branched hydrocarbon residue comprising
a carbon-carbon double bond, having three to six carbon atoms, provided
that the carbon atom of the attachment point of the C3-6 alkenyl to
the rest of the molecule is not bonded to another carbon atom of the
C3-6 alkenyl by a carbon-carbon double bond. An example of a
C3-6 alkenyl is 2-propenyl.

[0022]The term "C3-6-alkynyl," alone or in combination with other
groups, means a straight-chain or branched hydrocarbon residue comprising
a carbon-carbon triple bond, having three to six carbon atoms, provided
that the carbon atom of the attachment point of the C3-6 alkynyl to
the rest of the molecule is not bonded to another carbon atom of the
C3-6 alkynyl by a carbon-carbon triple bond. An example of a
C3-6 alkynyl is 2-propynyl.

[0024]The term "heterocyclyl," alone or in combination with other groups,
means a non-aromatic mono- or bi-cyclic radical of four to nine ring
atoms in which one to three ring atoms are heteroatoms independently
selected from N, O and S(O)n (where n is an integer from 0 to 2),
with the remaining ring atoms being C. The more preferred heterocyclyls
are piperidyl or 6-aza-spiro[2,5]oct-6yl.

[0025]The term "heterocyclyl-C1-3alkyl" means a C1-3 alkyl,
substituted by one heterocyclyl, as defined herein.

[0026]The term "optionally substituted heterocyclyl-carbonyl" refers to
the group Rv1--C(O)--, wherein Rv1 is a heterocyclyl as defined
herein, optionally substituted by one or more substituents independently
selected from the group consisting of C1-4 alkyl, halo C1-4
alkyl and halogen. In particular embodiments, the "optionally substituted
heterocyclyl-carbonyl" is pyrrolidinyl-carbonyl or
di-fluoro-azetidinyl-carbonyl.

[0027]The term "aryl," alone or combination with other groups, means
phenyl or naphthyl. The term "arylmethyl" means a phenyl-CH2-- or a
naphthyl-CH2 radical.

[0028]The term "phenyl-C1-3alkyl" means a C1-3 alkyl, as defined
herein, substituted by phenyl.

[0029]The term "arylcarbonyloxy-C1-6 alkyl" refers to the group
Rc1--C(O)--O--Rc2--, wherein Rc2 is a C1-6 alkylene
and Rc1 is an aryl, as defined above

[0030]The term "heteroaryl," alone or combination with other groups, means
an aromatic monocyclic- or bicyclic-aromatic radical of 5 to 10 ring
atoms having one to three ring heteroatoms independently selected from N,
O, and S, with the remaining ring atoms being C.

[0031]The term "heteroaryl-C1-3alkyl" means a C1-3 alkyl
substituted by a heteroaryl, as defined herein.

[0032]The term "C1-6 alkoxy-carbonyloxy" refers to the group
Ra2--C(O)--O--, wherein Ra2 is a C1-6 alkoxy as defined
above.

[0033]The term "bicyclic radicals" means radicals having two rings, in
which two or more ring atoms of one ring are ring carbon atoms of the
other ring.

[0037]Unless otherwise indicated, in reference to a particular group or
molecule, the term "substituted" refers to the fact that at least one of
the hydrogen atoms of that group or molecule is replaced by some other
substituent.

[0038]"Optional" or "optionally" means that the subsequently described
event or circumstance may but need not occur, and that the description
includes instances where the event or circumstance occurs and instances
in which it does not. For example, an "aryl group optionally substituted
with an alkyl group" means that the alkyl may but need not be present,
and the description includes situations where the aryl group is
substituted with an alkyl group and situations where the aryl group is
not substituted with the alkyl group.

[0039]"Pharmaceutically acceptable excipient" means an excipient that is
useful in preparing a pharmaceutical composition that is generally safe,
non-toxic and neither biologically nor otherwise undesirable, and
includes excipient that is acceptable for veterinary use as well as human
pharmaceutical use. A "pharmaceutically acceptable excipient" as used in
the specification and claims includes both one and more than one such
excipient.

[0040]The term "a therapeutically effective amount" of a compound means an
amount of compound that is effective to prevent, alleviate or ameliorate
symptoms of disease or prolong the survival of the subject being treated.
Determination of a therapeutically effective amount is within the skill
in the art. The therapeutically effective amount or dosage of a compound
according to this invention can vary within wide limits and may be
determined in a manner known in the art. Such dosage will be adjusted to
the individual requirements in each particular case including the
specific compound(s) being administered, the route of administration, the
condition being treated, as well as the patient being treated. In
general, in the case of oral or parenteral administration to adult humans
weighing approximately 70 Kg, a daily dosage of about 0.1 mg to about
5,000 mg, preferably from about 0.1 mg to about 1,000 mg, more preferably
from about 0.5 to 500 mg, and more preferably from about 1 mg to 100 mg,
should be appropriate, although the upper limit may be exceeded when
indicated. The daily dosage can be administered as a single dose or in
divided doses, or for parenteral administration, it may be given as
continuous infusion.

[0041]The term "pharmaceutically acceptable carrier" is intended to
include any and all material compatible with pharmaceutical
administration including solvents, dispersion media, coatings,
antibacterial and antifungal agents, isotonic and absorption delaying
agents, and other materials and compounds compatible with pharmaceutical
administration. Except insofar as any conventional media or agent is
incompatible with the active compound, use thereof in the compositions of
the invention are contemplated. Supplementary active compounds can also
be incorporated into the compositions.

[0042]Unless otherwise indicated, the term "a compound of the formula" or
"a compound of formula" or "compounds of the formula" or "compounds of
formula" refers to any compound selected from the genus of compounds as
defined by the formula.

[0053](7) C3-7 cycloalkyl, which is optionally substituted one to
three times by Rd, [0054](8) C3-7 cycloalkyl C1-6 alkyl,
wherein the C3-7 cycloalkyl portion of said C3-7 cycloalkyl
C1-6 alkyl is optionally substituted one to three times by Rd,
[0055](9) C7-10 bicycloalkyl, [0056](10) phenyl C1-3 alkyl,
wherein the phenyl portion of said phenyl C1-3 alkyl is optionally
substituted one to three times by Rd. [0057](11) heteroaryl
C1-3 alkyl, wherein the heteroaryl portion of said heteroaryl
C1-3 alkyl is optionally substituted one to three times by Rd.
[0058](12) heterocyclyl, which is optionally substituted one to three
times by Rd, and [0059](13) heterocyclyl C1-6 alkyl, wherein
the heterocyclyl portion of said heterocyclyl C1-6 alkyl is
optionally substituted one to three times by Rd; [0060]provided that
at least one of R1 and R2 is not hydrogen; or alternatively,
[0061]R1 and R2, together with the nitrogen atom to which they
are attached, form a heterocyclyl optionally substituted one to three
times by Rd, and wherein: (a) one of the ring carbon atoms of said
heterocyclyl formed by R1 and R2 is optionally replaced with a
carbonyl group; and/or (b) one of the ring carbon atoms of said
heterocyclyl formed by R1 and R2 is also a ring carbon atom of
another ring which is a C3-7 cycloalkyl or heterocyclyl, which is
optionally substituted by a C1-6 alkyl, and wherein one or two ring
carbon atoms of said C3-7 cycloalkyl or heterocyclyl is optionally
replaced by a carbonyl group; [0062]R3 and R4 are independently
selected from the group consisting of: [0063](1) hydrogen, [0064](2)
hydroxy, [0065](3) C1-6 alkyl, [0066](4) C1-6 alkoxy, [0067](5)
C3-7 cycloalkyl, [0068](6) C3-7 cycloalkyl C1-6 alkyl,
[0069](7) C1-6 alkoxycarbonyl, [0070](8) carboxyl, [0071](9)
carbamoyl, [0072](10) mono or di-C1-6 alkyl substituted carbamoyl,
[0073](11) C1-6 alkoxycarbonyloxy, [0074](12) mono or di-C1-6
alkyl substituted aminocarbonyloxy, [0075](13) hydroxy-C1-6 alkyl,
[0076](14) C1-6 alkoxy-C1-6 alkyl, [0077](15) halogen or halo
C1-6 alkyl, [0078](16) optionally substituted heterocyclyl-carbonyl,
and [0079](17) RaaRbbN--C(O)-- wherein Raa and Rbb
are independently selected from the group consisting of hydrogen,
C1-6 alkyl, hydroxy-C1-6 alkyl and C3-7 cycloalkyl; or
alternatively, [0080]R3 and R4, together with the carbon atom
to which they are attached, form C3-7 cycloalkyl or heterocyclyl
optionally substituted by one to three substituents independently
selected from the group consisting of C1-4 alkyl, halo C1-4
alkyl and halogen; [0081]R5 and R6 are independently hydrogen,
C1-6 alkyl or C3-7 cycloalkyl, wherein said C1-6 alkyl and
said C3-7 cycloalkyl are optionally substituted by one to three
substituents independently selected from the group consisting of: (1)
amino, (2) hydroxy, (3) carboxyl, (4) carbamoyl, (5) mono or di-C1-6
alkyl substituted carbamoyl and (6) C1-6 alkoxycarbonyl; or
alternatively R5 and R6, together with the carbon atom to which
they are attached, form C3-7 cycloalkyl or heterocyclyl;
[0082]R7, R8, R9 and R10 are independently hydrogen,
C1-6 alkyl, C3-7 cycloalkyl, or aryl; wherein said C1-6
alkyl is optionally substituted by one to three substituents
independently selected from the group consisting of: [0083](1) hydroxy,
[0084](2) C1-6 alkoxy, [0085](3) carboxyl, [0086](4) carbamoyl,
[0087](5) mono or di-C1-6 alkyl substituted carbamoyl, [0088](6)
C1-6 alkoxycarbonyl, [0089](7) aryl, optionally substituted by one
to three substituents independently selected from the group consisting of
halogen, C1-6 alkyl, halo C1-6 alkyl, C1-6 alkoxy and halo
C1-6 alkoxy, and [0090](8) heteroaryl, optionally substituted by one
to three substituents independently selected from the group consisting of
halogen, C1-6 alkyl, halo C1-6 alkyl, C1-6 alkoxy and halo
C1-6 alkoxy; [0091]Rd is selected from the group consisting
of: [0092](1) hydroxy, [0093](2) cyano, [0094](3) NRaRb,
[0095](4) halogen, [0096](5) C1-6 alkyl, [0097](6) halo C1-6
alkyl, [0098](7) hydroxy C1-6 alkyl, [0099](8) C1-6 alkoxy,
[0100](9) C1-6 alkoxy C1-6 alkyl, [0101](10) C3-7
cycloalkyl, [0102](11) C1-6 alkoxycarbonyl, [0103](12) acyl,
[0104](13) --C(O)NRaRb, [0105](14) --NRa--C(O)--Rb,
[0106](15) --NRa--C(O)--ORb, [0107](16)
--NRa--C(O)--NRb, [0108](17) --NRa--SO2--Rb,
[0109](18) --NRa--SO2--NRbRc, [0110](19)
--OC(O)NRaRb, [0111](20) --OC(O)ORa, [0112](21) C1-6
alkylsulfonyl, [0113](22) C1-6 alkylsulfinyl, [0114](23) C1-6
alkylthio, [0115](24) phenyl or phenyl C1-3 alkyl, wherein the
phenyl or phenyl portion of said phenyl C1-3 alkyl is optionally
substituted one to three times by a substituent independently selected
from the group consisting of hydroxy, cyano, NRaRb, halogen,
C1-6 alkyl, halo C1-6 alkyl, hydroxy C1-6 alkyl, C1-6
alkoxycarbonyl, acyl, --C(O)NRaRb, --NRa--C(O)--Rb,
--NRa--C(O)--ORb, --NRa--C(O)--NRb,
--NRa--SO2--Rb, --NRa--SO2--NRbRc,
--OC(O)NRaRb, --OC(O)ORa, C1-6 alkylsulfonyl,
C1-6 alkylsulfinyl, and C1-6 alkylthio; [0116](25) heteroaryl
or heteroaryl C1-3 alkyl, wherein the heteroaryl or heteroaryl
portion of said heteroaryl C1-3 alkyl is optionally substituted one
to three times by a substituent independently selected from the group
consisting of hydroxy, cyano, NRaRb, halogen, C1-6 alkyl,
halo C1-6 alkyl, hydroxy C1-6 alkyl, C1-6 alkoxycarbonyl,
acyl, --C(O)NRaRb, --NRa--C(O)--Rb,
--NRaC(O)--ORb, --NRa--C(O)--NRb,
--NRa--SO2--Rb, --NRa--SO2--NRbRc,
--OC(O)NRaRb, --OC(O)ORa, C1-6 alkylsulfonyl,
C1-6 alkylsulfinyl, and C1-6 alkylthio; and [0117](26)
heterocyclyl, which is optionally substituted one to three times by a
substituent independently selected from the group consisting of hydroxy,
cyano, NRaRb, halogen, C1-6 alkyl, halo C1-6 alkyl,
hydroxy C1-6 alkyl, C1-6 alkoxycarbonyl, acyl,
--C(O)NRaRb, --NRa--C(O)--Rb,
--NRa--C(O)--ORb, --NRa--C(O)--NRb,
--NRa--SO2--Rb, --NRa--SO2--NRbRc,
--OC(O)NRaRb, --OC(O)ORa, C1-6 alkylsulfonyl,
C1-6 alkylsulfinyl, and C1-6 alkylthio, and wherein one or two
ring carbon atoms of the heterocyclyl is optionally replaced with a
carbonyl group; [0118]Ra, Rb and Rc are independently
hydrogen or C1-6 alkyl; [0119]m is an integer of 0 to 3; n is an
integer of 0 to 3; m+n is an integer of 1 to 5; and [0120]p is 0 or 1.

[0121]Compounds that have the same molecular Formula but differ in the
nature or sequence of bonding of their atoms or the arrangement of their
atoms in space are termed "isomers." Isomers that differ in the
arrangement of their atoms in space are termed "stereoisomers".
Stereoisomers that are not mirror images of one another are termed
"diastereomers" and those that are non-superimposable mirror images of
each other are termed "enantiomers". When a compound has an asymmetric
center, for example, if a carbon atom is bonded to four different groups,
a pair of enantiomers is possible. An enantiomer can be characterized by
the absolute configuration of its asymmetric center and is described by
the R-- and S-sequencing rules of Cahn, Ingold and Prelog, or by the
manner in which the molecule rotates the plane of polarized light and
designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers
respectively). A chiral compound can exist as either individual
enantiomer or as a mixture thereof. A mixture containing equal
proportions of the enantiomers is called a "racemic mixture".

[0122]The compounds of formula (I) can possess one or more asymmetric
centers. Unless indicated otherwise, the description or naming of a
particular compound in the specification and claims is intended to
include both individual enantiomers and mixtures, racemic or otherwise,
thereof, as well as individual epimers and mixture thereof. The methods
for the determination of stereochemistry and the separation of
stereoisomers are well-known in the art (see discussion in Chapter 4 of
"Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons,
New York, 1992).

[0123]The compounds of formula (I) are CCR2 receptor antagonists, with
some antagonist activity also at CCR3 and CCR5.

[0124]While the broadest definition of this invention is described before,
certain compounds of formula (I) are preferred. [0125]i) In the compounds
of formula (I), A is preferably phenyl or naphthyl, said phenyl and said
naphthyl being optionally substituted by one to three substituents
independently selected from the group consisting of halogen, halo
C1-6 alkyl, halo C1-6 alkoxy and aryl. More preferably, A is
phenyl substituted by one or two substituents independently selected from
the group consisting of halogen, halo C1-6 alkyl and halo C1-6
alkoxy, most preferably selected from the group consisting of chloro,
trifluoromethyl, trifluoromethoxy. A is especially 3,4-dichlorophenyl,
3-chlorophenyl, 3-trifluoromethylphenyl, 3-Chloro-4trifluoromethylphenyl
or 3-trifluoromethoxylphenyl. [0126]ii) In the compounds of formula (I),
X is preferably --N(R1)(R2) and R1 and R2, together
with the nitrogen atom to which they are attached, form heterocyclyl
optionally substituted by one to three substituents independently
selected from the group consisting of hydroxy, C1-6 alkyl and
hydroxy C1-6 alkyl; and/or one of the ring carbon atoms of the
heterocyclyl formed by R1 and R2 may be a ring carbon atom of
another ring which is C3-7 cycloalkyl. The heterocyclyl formed by
R1 and R2, together with the nitrogen atom to which they are
attached, is preferably piperidyl or pyrrolidinyl, and said piperidyl and
pyrrolidinyl being optionally substituted by one or two substituents
independently selected from the group consisting of hydroxy, C1-5
alkyl and hydroxy C1-6 alkyl, and/or one of the ring carbon atoms of
said piperidyl and pyrrolidinyl formed by R1 and R2 may be
shared by C3-7 cycloalkyl, most preferably by a cyclopropyl ring.

[0127]More preferably, in the compounds of formula (I), X is a mono
spiro-heterocyclyl such as 6-aza-spiro[2,5]oct-6-yl,
5-azaspiro[2.5]oct-5-yl, 7-aza-spiro[3.5]non-7-yl,
8-aza-spiro[4.5]dec-8-yl, 1,8-diaza-spiro[4.5]dec-8-yl,
1,3,8-triaza-spiro[4.5]dec-8-yl, 2,8-diaza-spiro[4.5]dec-8-yl,
1-oxa-3,8-diaza-spiro[4.5]dec-8-yl, 1-oxa-8-aza-spiro[4.5]dec-8-yl,
2-oxa-8-aza-spiro[4.5]dec-8-yl, 2-oxa-7-aza-spiro[3.5]non-7-yl,
1-oxa-7-aza-spiro[3.5]non-7-yl, 9-aza-spiro[5.5]undec-9-yl,
1-oxa-4,9-diaza-spiro[5.5]undec-9-yl, wherein the spiro-heterocyclyl ring
is optionally substituted by one to three substituents independently
selected from the group consisting of hydroxy, oxo, alkoxy, fluoro or
C1-6 alkyl. Most preferably the spiro heterocyclyl is
6-aza-spiro[2,5]oct-6-yl wherein the spiro-heterocyclyl ring is
optionally substituted by one to two hydroxy.

[0128]In the compounds of formula (I), X is especially
(S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl. [0129]iii) In the compounds of
formula (I), m+n is an integer of 1, 2 or 3, more preferably m+n is an
integer of 2 or 3, most preferably m+n is 2. [0130]iv) In the compounds
of formula (I),one of R3 and R4 is preferably hydrogen and the
other is hydrogen, hydroxy, C1-6 alkoxycarbonyl, di-C1-6 alkyl
substituted carbamoyl, hydroxy-C1-6 alkyl, C1-6
alkoxy-C1-6 alkyl, N,N,Hydroxy-C1-6 alkyl-C1-6
alkyl-carbamoyl or N,N--C3-7 cycloalkyl, C1-6 alkyl-carbamoyl.
[0131]v) The compounds of formula (I), wherein n is 0, m is 2 and one of
R3 and R4 is hydrogen, and the other is hydrogen, C1-6
alkoxycarbonyl, hydroxy-C1-6 alkyl, C1-6 alkoxy-C1-6
alkyl, carboxyl or mono or di-C1-6 alkyl substituted carbamoyl, are
preferred. [0132]vi) In the compounds of formula (I), preferably, one or
two of R5, R6, R7, R8, R9 and R10 are
independently hydrogen, C1-6 alkyl, phenyl or optionally
trifluoromethyl substituted phenyl-C1-6 alkyl and the others are
hydrogen. More preferably, one of R5 and R6 is hydrogen or
C1-6 alkyl, the other is hydrogen, on of R9 and R10 is
hydrogen or C1-6 alkyl (preferably methyl), the other is hydrogen,
and R7, R8, are hydrogen. Even more preferably, one of R5
and R6 is hydrogen or C1-6 alkyl, the other is hydrogen, and
R7, R8, R9 and R10 are hydrogen.

[0149]Compounds of formula (I) can be produced as outlined in scheme 1. LG
is a leaving group, e.g., chloro, bromo, iodo, or methanesulfonyloxy.

[0150]Thus, heterocycle 1 is reacted with alkylating agent 2 in the
presence of a base, e.g., sodium hydride or potassium tert-butylate, in a
solvent such as N,N-dimethylformamide, N,N-dimethylacetamide or
tetrahydrofuran, at temperatures between 0° C. and 100° C.,
thus leading to (I).

[0152]Substituents R3 and/or R4 in (I) or in any synthetic
intermediate can be interconverted using reagents and methods known in
the art. For instance, esters (R3 and/or R4═C1-6
alkoxycarbonyl) can be reduced to the corresponding alcohols (R3
and/or R4=hydroxymethyl), e.g., with lithium borohydride in ethanol.
These alcohols can further be transformed to ethers (R3 and/or
R4═CH2OC1-6 alkyl), e.g., with an alkyl halide in
solvents such as tetrahydrofuran, N,N-dimethylformamide or
N,N-dimethylacetamide with sodium hydride as base, or with an alkyl
halide in the presence of silver(I) oxide. Similarly, esters (R3
and/or R4═C1-6 alkoxycarbonyl) can be hydrolyzed to the
corresponding carboxylic acids, (R3 and/or R4═COOH), e.g.,
through base-mediated hydrolysis using bases such as lithium hydroxide or
sodium hydroxide in solvents such as water, methanol, tetrahydrofuran, or
mixtures thereof. These acids can then be elaborated to the corresponding
amides (R3 and/or R4=mono- or di-C1-6 alkyl substituted
aminocarbonyloxy), as described in scheme 8, step b.

[0153]Compounds of formula (I) can also be synthesized as described in
scheme 2. PG2 is a protective group, e.g., benzyl,
tetrahydropyran-2-yl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl,
LG is a leaving group such as chloro, bromo, iodo, or methanesulfonyloxy.

[0154]In step a, scheme 2, heterocycle 1 is reacted with alkylating agent
3, leading to 4. The reaction is performed in analogy with scheme 1.

[0155]In step b, scheme 2, the protective group of the hydroxyl of 4,
PG2, is removed, using methods and reagents known in the art,
leading to 5. In the case where PG2 is benzyl, the protective group
is removed, e.g., by hydrogenation at pressures between 1 bar and 100
bar, in the presence of a suitable catalyst, e.g., palladium on activated
charcoal, in solvents such as methanol, ethanol, ethyl acetate, acetic
acid, or mixtures thereof, at temperatures between 20° C. and
150° C. In the case where PG2 is tetrahydropyran-2-yl, the
protective group is removed under acidic conditions, e.g., with
toluene-4-sulfonic acid, pyridinium toluene-4-sulfonate, or hydrochloric
acid, in solvents such as methanol, ethanol, water, or mixtures thereof,
at temperatures between 20° C. and 100° C. In the case
where PG2 is a silyl group, e.g., tert-butyldimethylsilyl or
tert-butyldiphenylsilyl, the protective group is removed with a fluoride
reagent, e.g., tetrabutylammonium fluoride, in a solvent such as
tetrahydrofuran, at temperatures between 0° C. and 50° C.
In the case where PG2 is a silyl group, e.g., tert-butyldimethylsilyl or
tert-butyldiphenylsilyl, and R3 and/or R4 is C1-6
alkoxycarbonyl, the protective group is preferably removed by reaction
with boron trichloride or boron tribromide in a solvent such as
dichloromethane, at temperatures between -78° C. and 40° C.

[0156]In step c, scheme 2, alcohol 5 is oxidized to aldehyde 6 using
reagents and method known in the art. For instance, the oxidation is
carried out with sodium hypochlorite, in a two-phase mixture of water and
dichloromethane, in the presence of sodium hydrogencarbonate and
catalytic amounts of sodium bromide or potassium bromide and
2,2,6,6-tetramethylpiperidin-1-oxyl radical, at temperatures between
0° C. and 25° C. Alternatively, the oxidation may be
performed with catalytic amounts of tetrapropylammonium perruthenate in
the presence of stoichoimetric amounts of a co-oxidant such as
4-methylmorpholine-4-oxide and molecular sieves, at temperatures between
0° C. and 40° C., in solvents such as dichloromethane,
acetonitrile or mixtures thereof. Alternatively, dimethyl sulfoxide-based
reagents can be employed, such as dimethyl sulfoxide-oxalyl chloride, or
dimethyl sulfoxide-trifluoroacetic anhydride, in the presence of an
organic base such as triethylamine in a solvent such as dichloromethane,
at temperatures below 0° C., typically between -78° C. and
-60° C. Alternatively, pyridine-sulfur trioxide can be employed in
dimethyl sulfoxide or dimethylsulfoxide-dichloromethane solvent mixture
in the presence of an organic base such as triethylamine, at temperatures
between 0° C. and 25° C.

[0157]In step d, scheme 2, aldehyde 6 is transformed into (I) by reaction
with amine HN(R1)(R2), using methods well known in the art,
e.g., reductive amination. The reaction is carried out using a suitable
reducing agent, e.g., sodium borohydride, sodium triacetoxyborohydride,
sodium cyanoborohydride, or borane pyridine complex, in solvents such as
methanol, ethanol, acetic acid, 1,2-dichloroethane, or mixtures thereof,
optionally in the presence of a dehydrating agent such as magnesium
sulfate, at temperatures between 0° C. and 80° C.

[0158]Amines of formula HN(R1)(R2) are either commercially
available or can be synthesized as described in the experimental section.

[0160]Compounds of formula (I) can be produced as outlined in scheme 3. A'
is aryl or heteroaryl, PG1 is a suitable protective group such as
tert-butoxycarbonyl or benzyloxycarbonyl, LG1 and LG2 are
leaving groups such as fluoro, chloro, bromo, iodo, or
trifluoromethanesulfonyloxy.

[0161]In step a, scheme 3, protected heterocycle 7 is reacted with
alkylating agent 2, leading to 8. The reaction is performed in analogy
with scheme 1.

[0162]In step b, scheme 3, the protective group of 8, PG1, is removed
using methods known in the art, leading to secondary amine 9. In the case
where PG1 is tert-butoxycarbonyl, suitable deprotection reagents and
conditions are strong acids such as hydrogen chloride or trifluoroacetic
acid in a solvent such as 1,4-dioxane or dichloromethane, at or below
room temperature. In the case where PG1 is benzyloxycarbonyl, the
protective group is removed by hydrogenation at pressures between 1 and
100 bar, at temperatures between 0° C. and 100° C., in
solvents such as methanol, ethanol, or ethyl acetate.

[0163]In step c, scheme 3, secondary amine 9 is converted to compound of
general formula (I) through reaction with halide or sulfonate 10A, with
boronic acid 10B, or with aldehyde 10C using reagents and methods known
in the art.

[0164]For instance, the reaction can be performed with halide or sulfonate
10A at temperatures between 20° C. and 200° C., in the
presence of a base, e.g., potassium carbonate, cesium carbonate or
triethylamine, in a solvent such as acetonitrile, N,N-dimethylformamide
or N-methylpyrrolidinone, optionally under microwave irradiation.

[0165]Alternatively, in the case where A is aryl or heteroaryl, the
reaction can be performed with halide or sulfonate 10A in the presence of
a copper(I) salt, e.g., copper(I)iodide, and a diol ligand, e.g.,
1,2-ethanediol, in a solvent such as 2-propanol, in the presence of a
base, e.g., potassium phosphate or cesium carbonate, at temperatures
between 60° C. and 90° C.

[0166]Alternatively, in the case where A is aryl or heteroaryl, the
reaction may be performed with halide or sulfonate 10A in the presence of
a palladium salt, e.g., palladium(II)chloride or palladium(II)acetate, a
phosphine ligand, e.g., 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl or
2',4',6'-triisopropyl-1,1'-biphenyl-2-yldicyclohexylphosphine, a base,
e.g., potassium phosphate, sodium methylate, or cesium carbonate, in a
solvent such as toluene or 1,4-dioxane, at temperatures between
20° C. and 110° C.

[0167]Alternatively, in the case where A is aryl or heteroaryl, the
reaction may be performed with arylboronic acid 10B in the presence of
anhydrous copper(II)acetate, in the presence of a base, e.g.,
triethylamine or pyridine, in a solvent such as dichloromethane, at
temperatures between 0° C. and 40° C., optionally in the
presence of molecular sieves.

[0168]Alternatively, in the case where A is arylmethyl or
heteroarylmethyl, the reaction may be performed with aldehyde 10C, in
analogy with scheme 2, step d.

[0170]Intermediate 8 can also be prepared as outlined in scheme 4.
PG1 is a suitable protective group such as tert-butoxycarbonyl or
benzyloxycarbonyl, PG2 is a protective group, e.g., benzyl,
tetrahydropyran-2-yl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl.
LG is a leaving group such as chloro, bromo, iodo, or methanesulfonyloxy.

[0171]In step a, scheme 4, heterocycle 7 is reacted with alkylating agent
3, leading to 11. The reaction is performed in analogy with scheme 1.

[0172]In step b, scheme 4, the protective group of the hydroxyl of 11,
PG2, is removed, leading to 12. This deprotection is performed in
analogy with scheme 2, step b.

[0176]Intermediate 4 in which R6, R8 and R10 are H and p is
1 is represented by the general formula 4A.

##STR00008##

[0177]A, R3, R4, R5, R7, R9, R10, m and n
are as defined before.

[0178]Intermediate 4A can be also synthesized as described in scheme 5.
Re is tert-butyl, benzyl, or lower alkyl, e.g., methyl or ethyl,
PG2 is a protective group, e.g., benzyl, tetrahydropyran-2-yl,
tert-butyldimethylsilyl or tert-butyldiphenylsilyl.

[0179]In step a, scheme 5, aldehyde or ketone 14 is transformed into 16 by
reaction with amine 15, using methods well known in the art, e.g.,
reductive amination. The reaction is carried out using a suitable
reducing agent, e.g., sodium borohydride, sodium triacetoxyborohydride,
sodium cyanoborohydride, or borane pyridine complex, in solvents such as
methanol, ethanol, acetic acid, 1,2-dichloroethane, or mixtures thereof,
at temperatures between 0° C. and 80° C.

[0180]Amines of formula 15 are either commercially available or can be
synthesized as described in the experimental section.

[0181]In step b, scheme 5, ester 16 is deprotected to give acid 17. In the
case where Re is tert-butyl, the deprotection is performed, e.g.,
with hydrogen chloride, in solvents such as 1,4-dioxane, water, or
mixtures thereof, at temperatures between 0° C. and 20° C.
In the case where Re is benzyl, the deprotection is performed, e.g.,
by hydrogenation at pressures between 1 bar and 10 bar, in solvents such
as methanol, ethanol, tetrahydrofuran, ethyl acetate, or mixtures
thereof, in the presence of a suitable catalyst, e.g., palladium on
activated charcoal. In the case where Re is lower alkyl, the
deprotection is performed, e.g., by base-mediated hydrolysis in solvents
such as water, methanol, tetrahydrofuran and mixtures thereof at
temperatures between -20° C. and 120° C. Typical reagents
are aqueous or lithium hydroxide, sodium hydroxide, potassium hydroxide,
sodium hydrogen carbonate, sodium carbonate, potassium hydrogencarbonate
and potassium carbonate.

[0182]In step c, scheme 5, amino acid 17 is cyclized to 4A using methods
well known to someone skilled in the art, e.g., amide formation using a
coupling reagent. The reaction is typically carried out in aprotic
solvents such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide,
N-methylpyrrolidinone and mixtures thereof in the presence or absence of
a base such as triethylamine, diisopropylethylamine, 4-methylmorpholine,
and/or 4-(dimethylamino)pyridine, at temperatures between -30° C.
and 60° C. Typically used coupling agents are
N,N'-dicyclohexylcarbodiimide,
1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride,
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluoro-phosphate
or O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluoro-phosphate.

[0183]Substituents R6 can be introduced in the ring system of 4A via
deprotonation of the proton at C(6) of the [1,4]diazepan-5-one ring under
suitable conditions (e.g., lithium hexamethyldisilazide or lithium
diisopropyl amide in a solvent like tetrahydrofuran at temperatures
between -78° C. and 0° C.), followed by selective
alkylation with an electrophile of the general formula R6-LG, in
which LG is a leaving group such as bromo, iodo, or
trifluoromethanesulfonyloxy.

[0185]Intermediate of formula 14 can be synthesized as outlined in scheme
6. LG1 and LG2 are leaving groups, e.g., chloro, bromo, or
iodo, Re is tert-butyl, benzyl, or lower alkyl, e.g., methyl or
ethyl.

[0186]In step a, scheme 6, aniline 18 is reacted with acrylate 19A or with
3-halopropionate 19B, leading to 20. The reaction with acrylate 19A is
either performed neat or in a solvent such as methanol, at temperatures
between 0° C. and 100° C. The reaction with
3-halopropionate 19B is preferably performed using a base, e.g.,
2,6-lutidine, in a solvent such as toluene or N,N-dimethylformamide, at
temperature between 60° C. and the boiling point of the solvent.

[0187]In step b, scheme 6, secondary amine 20 is alkylated with
2-halo-N-methoxy-N-methylacetamide 21, leading to 22. The reaction is
performed in a solvent such acetonitrile or N,N-dimethylformamide, in the
presence of a base, e.g., 2,6-lutidine or potassium carbonate, at
temperatures between 50° C. and 150° C.

[0188]N-Methoxy-N-methylamides 21 are commercially available or can be
synthesized from the corresponding acid by reaction with
N,O-dimethyl-hydroxyl-amine hydrochloride in analogy with scheme 8, step
b.

[0189]In step c, scheme 6, N-methoxy-N-methylamide 22 is converted to
ketone 14 using reagents and methods known in the art. For instance, 22
is reacted with the appropriate organomagnesium (R7--Mg-Hal, with
Hal=Cl, Br, I) or organolithium (R7--Li) reagent, in a solvent such
as tetrahydrofuran, at temperatures between -78° C. and
+60° C.

[0195]In step b, scheme 7, the sterically less hindered ester group of 24,
C(O)ORg, is selectively reduced, leading to alcohol 25. This
conversion is accomplished with a suitable reducing agent, e.g., lithium
borohydride, in a solvent such as methanol or ethanol, at temperatures
between 0° C. and 40° C.

[0198]Intermediate 5 in which p is 0, R8 and R10 are H is
represented by the general formula 5A.

##STR00013##

[0199]R3, R4, R5, R6, R7, R9, m and n are as
defined before.

[0200]Intermediate 5A can be also synthesized as described in scheme 8.
Re is lower alkyl, e.g., methyl or ethyl, PG2 is a protective
group, e.g., benzyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or
tetrahydropyran-2-yl, LG is a leaving group, e.g., chloro or bromo.

[0201]In step a, scheme 8, primary amine 15 is converted to secondary
amine 27 by reductive amination reaction with carbonyl derivative 26A or
by nucleophilic substitution reaction with halide 26B. The reductive
amination reaction with 26A is performed in analogy with scheme 5, step
a. The nucleophilic substitution reaction with 26B is performed, e.g., in
a solvent such as methanol, ethanol, or acetonitrile, at temperatures
between 20° C. and the boiling point of the solvent, in the
presence of a base, e.g., potassium hydrogencarbonate, potassium
carbonate, optionally in the presence of sodium iodide.

[0202]In step b, scheme 8, secondary amine 27 is converted to amide of
general formula 29 through reaction with N-aryl amino acid 28 using
methods well known to someone skilled in the art. For instance, the
reaction is carried out in the presence of a coupling agent such as
N,N'-dicyclohexylcarbodiimide,
1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride,
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluoro-phosphate,
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluoro-phosphate or bromo-tris-pyrrolidino-phosphonium
hexafluorophosphate, in aprotic solvents such as dichloromethane,
tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone and
mixtures thereof at temperatures between -40° C. and 80° C.
in the presence or absence of a base such as triethylamine,
diisopropylethylamine, 4-methylmorpholine, and/or
4-(dimethylamino)pyridine.

[0203]Alternatively, this reaction can be performed in two steps involving
first formation of the acyl halide derivative of 28 and subsequent
coupling reaction with amine 27 in the presence of a base. Typically
employed reagents for the formation of the acyl chloride are thionyl
chloride, phosphorus pentachloride, oxalyl chloride or cyanuric chloride,
and the reaction is generally conducted in the absence of a solvent or in
the presence of an aprotic solvent like dichloromethane, toluene or
acetone. A base can optionally be added, like for example pyridine,
triethylamine, diisopropylethylamine or 4-methylmorpholine, and catalytic
amounts of N,N-dimethylformamide may be used. The obtained acyl chloride
can be isolated or reacted as such with amine 27 in an aprotic solvent,
like dichloromethane, tetrahydrofuran or acetone, in the presence of a
base. Typical bases are triethylamine, 4-methylmorpholine, pyridine,
diisopropylethylamine or 4-(dimethylamino)pyridine or mixtures thereof.

[0204]Alternatively, such reactions can be performed in two steps
involving first formation of a mixed anhydride derivative of 28 obtained
by reaction with a reagent such as ethyl chloroformate, isobutyl
chloroformate, or acetic anhydride, in a solvent such as dichloromethane
or tetrahydrofuran, at temperatures between -30° C. and 20°
C., and subsequent reaction with amine 27 as described above.

[0205]In the case where the presence of a hydroxy group in R3 or
R4 (e.g., R3 or R4=hydroxy or hydroxymethyl) may interfere
with the amide coupling reaction of step b, the hydroxyl of 27 may be
temporarily protected as the trimethylsilyl ether by reaction with
chlorotrimethylsilane, in the presence of a base, e.g., triethylamine of
N-methylmorpholine.

[0206]N-Aryl amino acids 28 are commercially available or can be
synthesized as described in the experimental section.

[0207]In step c, scheme 8, cleavage of the acetal and reductive
cyclization of 29 leads to piperazinone 5A. This conversion is performed
either in one step using an acid, e.g., trifluoroacetic acid or
methanesulfonic acid, and a reducing agent such as sodium borohydride or
triethylsilane, in solvents such as dichloromethane, 1,4-dioxane,
tetrahydrofuran, water, or mixtures thereof. Alternatively, the reaction
may be performed in two steps, by first forming a
3,4-dihydro-1H-pyrazin-2-one intermediate in the presence of an acid,
e.g., trifluoroacetic acid or methanesulfonic acid, in a solvent such as
water or dichloromethane, and subsequent catalytic hydrogenation at
pressures between 1 bar and 10 bar, using a suitable catalyst, e.g.,
palladium on activated charcoal, in solvents such as methanol, ethanol,
ethyl acetate, or mixtures thereof, at temperatures between 0° C.
and 50° C.

[0209]Compound (I) in which p is 0, R8 and R10 are H is
represented by the general formula (IA).

##STR00015##

[0210]A, X, R3, R4, R5, R6, R7, R9, m and n
are as defined before.

[0211]Compounds (IA) can be also synthesized as described in scheme 9.
PG3 is a suitable protective groups such as tert-butoxycarbonyl or
benzyloxycarbonyl, LG is a leaving group, e.g., chloro or bromo, Re
is lower alkyl, e.g., methyl or ethyl.

[0218]In step f, scheme 9, cleavage of the acetal, and reductive
cyclization of 35 leads to piperazinone (IA). This conversion is
performed in analogy with scheme 8, step c.

[0219]Intermediates 30, 31, and 32 may contain one ore more hydroxy
groups. It may be convenient to convert one or more of these hydroxy
groups to silyl ethers, e.g., triethylsilyl, tert-butyldimethylsilyl, or
tert-butyldiphenylsilyl. This conversion can be performed using methods
known in the art, as described in the experimental section. The removal
of such protective groups can take place under the acidic reaction
conditions of step f. Otherwise, the deprotection reaction is performed
using methods and reagents known in the art. Preferred reagents are
hydrogen fluoride-pyridine in acetonitrile at 20-80° C., or
tetrabutylammonium fluoride in tetrahydrofuran, at 20-60° C.

[0223]Compounds of formula 5B can also be prepared as described in scheme
10. Rf and Rg are independently hydrogen or C1-6 alkyl,
PG2 is a protective group, e.g., benzyl, tert-butyl-dimethylsilyl or
tert-butyl-diphenylsilyl.

[0224]In step a, scheme 10, removal of the protective group, PG2, of
4A and lactonization leads to intermediate 36. This reaction is
performed, e.g., in the presence of boron tribromide, in a solvent such
as dichlormethane, at temperatures between -78° C. and 20°
C. Alternatively, in the case where PG2 is tert-butyl-dimethylsilyl
or tert-butyl-diphenylsilyl, fluoride reagents, e.g., tetrabutylammonium
fluoride, may be used, in solvents such as tetrahydrofuran, at
temperatures between 0° C. and 50° C.

[0225]In step b, scheme 10, the lactone ring of 36 is opened with amine of
formula HN(Rf)(Rg), leading to hydroxyamide 5B. The reaction is
carried out with or without solvent (e.g., water, methanol, ethanol,
tetrahydrofuran, toluene, or mixtures thereof), at temperatures between
-20° C. and 150° C., optionally in the presence of
catalytic amounts of 2-hydroxypyridine. Alternatively, the amines may be
substituted by their hydrochloride salts, HN(Rf)(Rg).HCl, and
the reaction is carried out as described above and, in addition, in the
presence of a base, e.g., triethylamine.

[0227]Intermediates of formula 6 may also be prepared as outlined in
scheme 11. LG is a leaving group, e.g., chloro, bromo, iodo, or
methanesulfonyloxy.

[0228]In step a, scheme 11, heterocycle 1 is reacted with alkylating agent
37, leading to 38. The reaction is performed in analogy with scheme 1.

[0229]In step b, scheme 11, aldehyde 6 is obtained from alkene 38 by
oxidation using methods known in the art. Preferably, 38 is reacted with
sodium periodate in the presence of catalytic amounts of a suitable
osmium source such as osmium(VIII) oxide or potassium osmate(VI)
dihydrate, in solvents such as acetone, tert-butylalcohol, water, or
mixtures thereof, at temperatures between 0° C. and 30° C.

[0231]Intermediates of formula 1 may be prepared as outlined in scheme 12.
A' is aryl or heteroaryl, PG1 is a suitable protective group, e.g.,
benzyloxycarbonyl or tert-butoxycarbonyl, LG is a leaving group, e.g.,
fluoro, chloro, bromo, iodo or trifluoromethanesulfonyloxy.

[0232]In step a, scheme 12, the protective group of 7 is removed in
analogy with scheme 3, step b, leading to 39.

[0235]Intermediate 7 in which p is 1 is represented by the general formula
7A.

##STR00021##

[0236]R5, R6, R7, R8, R9 and R10 are as
defined before.

[0237]Intermediates 7A are commercially available or can be synthesized as
outlined in scheme 13. PG1 and PG2 are suitable orthogonal
protective groups, e.g., benzyloxycarbonyl and tert-butoxycarbonyl,
Re is lower alkyl, e.g., methyl or ethyl.

[0238]In step a, scheme 13, protected 1,2-diaminoethane derivative 40 is
reacted with acrylate 19A, leading to 41. The reaction is performed
either neat or, preferably, in a solvent such as methanol, at
temperatures between 0° C. and 50° C.

[0239]In step b, scheme 13, the amino group of 41 is protected, using
reagents and methods known in the art, thus leading to 42. In the case
where PG1 is tert-butoxycarbonyl, the reaction is carried out, e.g.,
with di-tert-butyl dicarbonate, in a solvent such as dichloromethane or
N,N-dimethylformamide, optionally in the presence of a base, e.g.,
triethylamine. In the case where PG1 is benzyloxycarbonyl, the
reaction is performed, e.g., with N-(benzyloxycarbonyloxy)succinimide or
with benzyl chloroformate, in solvents such as water, ethyl acetate,
acetone, tetrahydrofuran, or mixtures thereof, in the presence of a base,
e.g., triethylamine, sodium hydrogencarbonate, or potassium carbonate.

[0240]In step c, scheme 13, the protective group of the terminal amino
group, PG2, is removed and the resulting aminoester cyclized to
[1,4]diazepan-5-one 7AA, using methods and reagents known in the art. In
the case where PG2 is tert-butoxycarbonyl, the deprotection is
preferably accomplished using concentrated aqueous hydrochloric acid
solution, in a solvent such as ethyl acetate, at temperatures between
0° C. and 80° C. The aminoester hydrochloride intermediate
is then cyclized under suitable conditions. For instance the reaction is
carried out in the presence of an inorganic base, e.g., sodium carbonate,
in a solvent such as water or methanol, at temperatures between
20° C. and 80° C. Alternatively, the reaction is performed
in the presence of an organic base, e.g.,
1,5,7-triaza-bicyclo[4.4.0]dec-5-ene, in a solvent such as
dichloromethane or tetrahydrofuran, at temperatures between 0° C.
and 40° C.

[0241]In optional step d, scheme 13, substituents R6 can be
introduced in the ring system of 7AA, leading to 7A. This is accomplished
through double deprotonation of the protons at N(4) and C(6) of the
[1,4]diazepan-5-one ring under suitable conditions (e.g., lithium
hexamethyldisilazide or lithium diisopropyl amide in a solvent like
tetrahydrofuran at temperatures between -78° C. and 0° C.),
followed by selective alkylation with an electrophile of the general
formula R6-LG, in which LG is a leaving group such as bromo, iodo,
or trifluoromethanesulfonyloxy, thus leading to 7A.

[0243]Compounds of formula 40 are commercially available or can be
synthesized as described in the experimental section. In particular,
compounds of formula 40 where R7, R8, R9 are H, R10
is CH3, and the asymmetric carbon has the (R)-configuration are
represented by formula 40A. Compounds of formula 40A may be prepared from
commercially available (R)-1,2-diaminopropane dihydrochloride (43) as
outlined in scheme 14. PG2 is a suitable protective group, e.g.,
benzyloxycarbonyl or tert-butoxycarbonyl.

[0244]In the case where PG2 is tert-butoxycarbonyl, the reaction is
performed using a slight excess, preferably 1.25 equivalents of
di-tert-butyl dicarbonate and a slight excess of a base, e.g., sodium
hydroxide, preferably ca. 1.3 equivalents. The reaction is carried out in
a suitable solvent, e.g., water, methanol, ethanol, or mixtures thereof,
preferably in ethanol/water at a ratio between 1:1 and 2:1, at
temperatures between 0° C. and 25° C.

##STR00023##

[0245]Intermediate 1 in which R7, R8 and R10 are H and p is
0 is represented by formula 1A.

##STR00024##

[0246]Intermediates 1A can also be synthesized as outlined in scheme 15.
LG1 and LG2 are leaving groups, e.g., chloro or bromo.

[0247]In step a, scheme 15, aniline 18 is alkylated with haloacetonitrile
44, leading to 45. This reaction is performed in the presence of a base,
e.g., sodium carbonate or potassium carbonate, in a solvent such as
acetonitrile or N,N-dimethylformamide, optionally in the presence of
sodium iodide, at temperatures between 20° C. and 150° C.

[0248]In step b, scheme 15, nitrile 45 is reduced to primary amine 46,
using reagents and methods known in the art. For instance, the reaction
is performed in the presence a suitable reducing agent such as of
borane-tetrahydrofuran complex or lithium aluminum hydride, in a solvent
such as tetrahydrofuran, at temperatures between -20° C. and
60° C.

[0250]In step d, scheme 15, compound 48 is cyclized to 1AA, using reagents
and methods known in the art. For instance, the reaction is performed in
the presence of a base, e.g., sodium hydrogencarbonate or potassium
carbonate, in a suitable solvent, e.g., acetone, acetonitrile, methanol,
or ethanol, optionally in the presence of sodium iodide, at temperatures
between 20° C. and 100° C.

[0251]In optional step e, scheme 15, substituents R6 can be
introduced in the ring system of 1AA, leading to 1A. This is accomplished
through double deprolonation of the protons at N(1) and C(3) of the
piperazin-2-one ring under suitable conditions (e.g., lithium
hexamethyldisilazide or lithium diisopropyl amide in a solvent like
tetrahydrofuran at temperatures between -78° C. and 0° C.),
followed by selective alkylation with an electrophile of the general
formula R6-LG, in which LG is a leaving group such as bromo, iodo,
or trifluoromethanesulfonyloxy.

##STR00025##

[0252]In Scheme 15, A, R5, R6, and R9 are as defined
before.

[0253]Intermediate 4A in which R7 is H is represented by the general
formula 4AA.

##STR00026##

[0254]A, R3, R4, R5, R9, m and n are as defined
before.

[0255]Intermediate 4AA can be also synthesized as described in scheme 16.
Re is tert-butyl, benzyl, or lower alkyl, e.g., methyl or ethyl,
LG2 is a leaving group such as fluoro, chloro, bromo, iodo, or
trifluoromethanesulfonyloxy, PG2 is a protective group, e.g.,
benzyl, tetrahydropyran-2-yl, tert-butyldimethylsilyl or
tert-butyldiphenylsilyl.

[0256]In step a, scheme 16, halide or sulfonate 10A is transformed into 50
by reaction with amino acid 49, using methods well known in the art,
e.g., Ullmann-type coupling reaction. The reaction is carried out using a
suitable catalyst, e.g., copper iodide, optionally in the presence of
2-hydroxybenzaldehyde phenylhydrazone with a base like potassium
phosphate, in solvents such as N,N-dimethylformamide or
N,N-dimethylacetamide, at temperatures between 0° C. and
150° C., preferably at 80-100° C.

[0257]Compounds of formula 10A and amino acids 49 are either commercially
available or can be synthesized as described in the experimental section.

[0258]In step b, scheme 16, acid 50 is reduced to give alcohol 51, e.g.,
with borane-tetrahydrofuran complex, in solvents such as tetrahydrofuran
at temperatures between 0° C. and 20° C.

[0259]In step c, scheme 16, alcohol 51 is oxidized to the corresponding
aldehyde, as described in scheme 2, step c. The aldehyde intermediate is
immediately reacted with amine 15 to give intermediate 52, in analogy to
scheme 2, step d.

[0260]In step d, scheme 16, secondary amine 52 is converted to amide of
general formula 54 through reaction with acid 53 using methods well known
to someone skilled in the art. For instance, the reaction is carried out
in the presence of a coupling agent such as 2-chloro-1-methylpyridinium
iodide in the presence of tributylamine as a base, in aprotic solvents
such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide,
N-methylpyrrolidinone and mixtures thereof at temperatures between
0° C. and room temperature.

[0261]Acids 53 are commercially available or can be synthesized from the
corresponding ester or as described in the experimental section.

[0262]In step e, scheme 16, cleavage of the acetal and reductive
cyclization of 54 leads to ring system 4AA. This conversion is performed
in one step using an acid, e.g., trifluoroacetic acid, methanesulfonic
acid, and/or boron trifluoride etherate, and a reducing agent such as
triethylsilane, in a solvent such as dichloromethane.

[0264]Compounds of formula (I) in which R3 is OH, R4 is H, and m
is 1 are represented by general formula (IB)

##STR00028##

[0265]A, R5, R6, R7, R8, R9, R10, X, n and p
are as defined before.

[0266]Compounds of formula (IB) can also be synthesized as described in
scheme 17. W is methyl, trifluoromethyl, phenyl, or 4-methylphenyl.

[0267]In step a, scheme 17, diol 5C is converted to sulfonate 55 by
selective reaction with an appropriate sulfonyl halide, e., g.,
methanesulfonyl chloride (in the case where W is methyl). This reaction
is performed in the presence of a suitable base, e.g., pyridine,
2,4,6-trimethylpyridine or triethylamine, in a solvent such as
dichloromethane, tetrahydrofuran, or N,N-dimethylacetamide, at
temperatures between -78° C. and 20° C.

[0268]In step b, scheme 17, sulfonate 55 is converted to epoxide 56
through intramolecular cyclization. This reaction is performed in the
presence of a suitable base, e.g., sodium hydride or lithium
bis(trimethylsilyl)amide, in a solvent such as tetrahydrofuran or
N,N-dimethylacetamide, at temperatures between -20° C. and
50° C.

[0269]In step c, epoxide 56 is converted to (IB) by reaction with an amine
of the general formula HN(R1)(R2). This reaction is performed
in the presence of a suitable base, e.g., potassium carbonate, cesium
carbonate and/or N,N-diisopropylethylamine, in a solvent such as
tetrahydrofuran or N,N-dimethylacetamide, at temperatures between
0° C. and 150° C.

[0271]Compounds of formula I can have one or more asymmetric carbon atoms
and can exist in the form of optically pure enantiomers, mixtures of
enantiomers such as, for example, racemates, optically pure
diastereoisomers, mixtures of diastereoisomers, diastereoisomeric
racemates or mixtures of diastereoisomeric racemates. The optically
active forms can be obtained for example by resolution of the racemates,
by asymmetric synthesis or asymmetric chromatography (chromatography with
a chiral adsorbent or eluent). The invention embraces all of these forms.

[0283]For the assay cells were grown overnight in 384-well black clear
flat bottom polystyrene plates (Costar) at 37° C. at 5% CO2.
After washing with DMEM, 20 mM Hepes, 2.5 mM probenecid, 0.1% BSA (DMEM
assay buffer) cells were loaded with 4 μM Fluo-4 in the same DMEM
assay buffer for 2 hours at 30° C. Excess dye was removed and
cells were washed with DMEM assay buffer. 384-well compound plates were
prepared with DMEM assay buffer/0.5% dimethyl sulfoxide with or without
various concentrations of test compounds. Usually compounds were tested
for agonist and antagonist activity.

[0284]Test compounds were added to the assay plate and agonist activity
was monitored as fluorescence for 80 seconds with a FLIPR (488 nm
excitation; 510-570 nm emission; Molecular Devices). After 20-30 min. of
incubation at 30° C., 20 nM MCP-1 (R&D; Roche) was added and
fluorescence was monitored again for 80 seconds. Increases in
intracellular calcium are reported as maximum fluorescence after agonist
exposure minus basal fluorescence before exposure. Antagonist activity is
indicated as inhibitor concentration required for 50% inhibition of
specific calcium increases.

[0285]The compounds of formula (I) of the present invention exhibit
IC50 values in the Ca mobilization assay of 1 nM to 10 μM,
preferably 1 nM to 1.5 μM for CCR2. The following table shows measured
values for some selected compounds of the present invention.

[0286]The compounds of formula (I) and/or their pharmaceutically
acceptable salts can be used as medicaments, e.g. in the form of
pharmaceutical preparations for enteral, parenteral or topical
administration. They can be administered, for example, perorally, e.g. in
the form of tablets, coated tablets, dragees, hard and soft gelatine
capsules, solutions, emulsions or suspensions, rectally, e.g. in the form
of suppositories, parenterally, e.g. in the form of injection solutions
or suspensions or infusion solutions, or topically, e.g. in the form of
ointments, creams or oils. Oral administration is preferred.

[0287]The production of the pharmaceutical preparations can be effected in
a manner which will be familiar to any person skilled in the art by
bringing the described compounds of formula I and/or their
pharmaceutically acceptable salts, optionally in combination with other
therapeutically valuable substances, into a galenical administration form
together with suitable, non-toxic, inert, therapeutically compatible
solid or liquid carrier materials and, if desired, usual pharmaceutical
adjuvants.

[0290]The dosage of the compounds of formula (I) can vary within wide
limits depending on the disease to be controlled, the age and the
individual condition of the patient and the mode of administration, and
will, of course, be fitted to the individual requirements in each
particular case. For adult patients a daily dosage of about 1 to 1000 mg,
especially about 1 to 300 mg, comes into consideration. Depending on
severity of the disease and the precise pharmacokinetic profile the
compound could be administered with one or several daily dosage units,
e.g. in 1 to 3 dosage units.

[0295]A solution of 2.89 g (8.85 mmol) of
(S)-4-(tert-butyl-dimethyl-silanyloxy)-2-methanesulfonyloxy-butyric acid
methyl ester in 90 ml of 2-butanone was treated with 2.65 g (17.70 mmol)
of sodium iodide and stirred at 90° C. for 11/4 h. The reaction
was cooled, filtered and evaporated. The residue was suspended in
CH2Cl2 treated with Na2SO4 and filtered to give after
evaporation 2.94 g (93%) of the title compound as dark brown oil. MS:
343.0 (M-CH3).sup.+.

[0296]To a solution of diethylzinc (1.1 M solution in toluene, 37.5 ml,
0.04 mmol) in DCE (80 ml) at 0° C. was added chloroiodomethane
(5.99 ml, 0.08 mmol) under Ar. This mixture was stirred for 15 minutes
before a solution of 3-hydroxy-4-methylene-piperidine-1-carboxylic acid
tert-butyl ester (J. Org. Chem. 2001, 66, 2487) (4.19 g, 19.6 mmol) in
DCE (10 ml) was added, after which time the reaction was stirred for 0.5
h at 0° C. and then allowed to reach RT, stirring for a further 1
h. The reaction was then quenched by addition of sat. aq. ammonium
chloride solution, separated, and the organic dried (Na2SO4)
and concentrated. Purification by flash column chromatography
(EtOAc/heptane 2:8→1:1) afforded the title product (2.4 g, 54%) as
a crystalline solid. MS: 228.2 (MH.sup.+).

Method B

[0297]2 g (9.4 mmol, 1 eq.) 3-hydroxy-4-methylene-piperidine-1-carboxylic
acid tert-butyl ester were dissolved in toluene at 25° C. 17.05 ml
(2 eq.) 1.1 M diethyl zinc solution in toluene were added at such a rate
as to maintain the reaction temperature below 30° C. After 15-30
min at 25° C., 2.29 ml (3 eq.) diiodomethane were added over 2-3 h
maintaining the reaction temperature at 25° C. (the reaction is
best followed by Tr-Tj measurements and/or in-line FTIR reaction
monitoring). After 30-60 min after the end of addition, 4.57 ml
2-ethyl-hexanoic acid were added to the resulting white suspension at
such a rate as to maintain the reaction temperature between 25-30°
C. The heavy white suspension was stirred for 30 min. 10 ml heptane were
added followed by a mixture consisting of 20 ml 25% aq. ammonia solution
and 30 ml water. The organic phase was separated and washed with a
mixture consisting of 10 ml 25% aq. ammonia solution and 30 ml water. The
organic phases were washed with 20 ml half sat. aq. NaCl solution,
combined, dried over sodium sulfate, filtered and concentrated under
reduced pressure to an oil (may crystallize upon standing). The crude
spiro-piperidinol was purified by crystallization in heptane or
alternatively in TBME/heptane providing the title product in ca 80% yield
as a white powder.

[0303]D(+)-glucose monoydrate (300 g) and magnesium chloride hexahydrate
(1.0 g) were dissolved in 10 mM MES buffer pH 6.5 (2.4 L; Sigma M3671).
After addition of 4-oxo-6-aza-spiro[2.5]octane-6-carboxylic acid
tert-butyl ester (300 g; 1.33 mmol) and quadrature-NAD (3.0 g; free
acid; Roche Diagnostics Cat. No. 10 004 626) the pH was re-adjusted and
the suspension heated to 35° C. The reaction was started by adding
ketoreductase KRED-NADH-117 (3.0 g; former Biocatalytics, now Codexis)
and glucose dehydrogenase GDH-102 (300 mg; Biocatalytics). The suspension
was vigorously stirred at 35° C. keeping the pH constant at 6.5 by
the controlled addition (pH-stat) of 1.0 M aq. sodium hydroxide solution.
After a consumption of 1.307 L (corresponding to 98% conversion; after 17
h) the reaction mixture was extracted with EtOAc (10 L). The organic
phase was dried over sodium sulfate and concentrated in vacuo (200
mbar/45° C.) until evaporation fell off. Upon cooling the oily
residue (411 g) started to crystallize and was stirred with heptane (1 L)
for 2 h. The crystals were filtered off and the filtrate evaporated to
dryness, redissolved in EtOAc (150 ml) and concentrated in vacuo as
described above. The crystal suspension formed again upon cooling was
stirred with heptane (200 ml; 2 h) and the crystals filtered off. Both
crops of crystals were washed with heptane and dried under high vacuum to
yield the title compound in 93% yield (250.77 g and 34.60 g white
crystals), each having a purity of >98.5% GC and 99.8% ee.
[α]D=-44.97° (c=1.00, CHCl3).

[0309]6.9 g (36.34 mmol, 1 eq., 96% a % by GC)
1-allyl-cyclopropanecarboxylic acid tert-butyl ester were dissolved in 40
ml CH2Cl2 and 40 ml MeOH. The solution was cooled to
-72° C. and the ozone was bubbled through the reaction mixture
until a blue color was obtained. Then nitrogen was bubbled to remove
excess ozone until a colorless solution was obtained. 10 ml (3.68 eq.)
dimethyl sulfide and 14 ml (2.76 eq.) triethylamine were added. The
reaction mixture was warmed to RT and stirred overnight at that
temperature (peroxide test negative, pH 7-8). The yellowish reaction
mixture was added to 100 ml sat. aq. ammonium chloride solution
(exothermic) and extracted 3 times with 70 ml CH2Cl2. The
organic phases were combined, dried over sodium sulfate, filtered and
concentrated under reduced pressure to provide the crude aldehyde, which
was purified by filtration over SiO2 (CH2Cl2; TLC:
EtOAc/heptane 1:2) to provide 3.90 g (96% GC, 56% yield) of the title
compound as an oil.

[0313]100 mg (S)-6-benzyl-6-aza-spiro[2.5]octan-4-ol were dissolved in 1
ml MeOH and hydrogenated over palladium on barium sulfate. After
de-benzylation (IPC by GC), the catalyst was filtered and the filtrate
was concentrated under reduced pressure to provide the title compound.
The amino alcohol was treated with di-tert-butyl-dicarbonate in MeOH in
the presence of triethylamine. The crude tert-butoxycarbonyl-protected
amine product was analyzed by chiral GC (BGB-176; 30 m×0.25 mm;
80° C. to 210° C. in 43 min) and proved to be identical
with intermediate 2b.

[0314]The hydrochloride salt of the title compound can be obtained by
treating the aminoalcohol with HCl in EtOAc.

Preparation of N-benzylglycine tert-butyl ester

[0315]40 g (205 mmol, 1 eq.) tert-butyl bromoacetate were dissolved in 200
ml CH3CN. The solution was cooled to 0-5° C. and 47 g
benzylamine (2.14 eq.) in solution in 90 ml CH3CN were added over 15
min. After 5 min, the reaction mixture was warmed to RT and stirred for 3
h (IPC by GC). The resulting suspension was filtered and evaporated to
constant weight to give 49 g of a yellow oil. The oil was dissolved in
200 ml heptane and washed 3 times with 50 ml aq. NaHCO3 solution.
The organic phase was dried over sodium sulfate, filtered and evaporated
to give 35.8 g of the crude product. Distillation under high vacuum
afforded 27.2 g of the title product (95% pure by GC).

[0318](rac, trans)-4-Methyl-3-(4-nitro-benzoyloxy)-piperidine-1-carboxylic
acid tert-butyl ester (5.0 g, 14 mmol) was dissolved in MeOH (70 ml) and
6 M aq. sodium hydroxide solution (4.5 ml, 27 mmol) was added. The
reaction was stirred for 1 h after which time the solvent removed under
vacuum, the residue portioned between water and CH2Cl2 and the
organic collected, dried (Na2SO4) and concentrated to afford
the title product (2.6 g, 87%) as a crystalline solid. MS: 216.1
(MH.sup.+).

d) (3S,4S)-4-Methyl-piperidin-3-ol; hydrochloride

[0319](rac, cis)-3-Hydroxy-4-methyl-piperidine-1-carboxylic acid
tert-butyl ester was separated on a Chiralpak AD column
(Isopropanol/Heptane 5:95) and subsequently, the (-)-enantiomer was
deprotected with HCl in dioxane to afford the title compound as a white
powder. MS: 116.2 (MH.sup.+).

[0323]To a solution of (S)-1-benzyl-5-methyl-piperidin-3-one (0.9 g, 4
mmol) was dissolved in MeOH, 25% aq. HCl solution added until the pH was
acidic, followed by palladium (10% on activated charcoal, 0.2 g). The
mixture was stirred under 1 atmosphere of hydrogen (balloon) for 6 h. The
reaction was then filtered through Hyflo and concentrated to afford the
title product as a white powder (0.66 g, quant). MS (ISP)=116.1
(M+H).sup.+.

Intermediate 5

(S)-2-Amino-4-benzyloxy-butyric Acid methyl ester; hydrochloride

[0324]15.5 ml of acetyl chloride was added dropwise to 95 ml of MeOH
cooled in ice. The solution was stirred for 5 min and 15.47 g (73.91
mmol) O-benzyl-L-homoserine was added in one portion (in analogy to
Synthesis 1997, 10, 1146). The mixture was stirred at RT for 1 h, and
warmed for 21/2 h at reflux. The solution was cooled and the solvent
removed by evaporation under reduced pressure. The residue was dissolved
in CH2Cl2 and evaporated and dried under reduced pressure
overnight to give 19.41 g (quantitative) of the title compound as white
solid. MS: 224.1 (MH.sup.+).

[0325]A solution of 8.52 g (39.75 mmol) of
5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester in 200 ml of DMA
was treated at 0° C. with 2.60 g (59.6 mmol) of NaH (55%
dispersion in oil) in small portions. The reaction was stirred 1 h at
this temperature, then the free 1-(3-chloropropyl)piperidine in 200 ml
toluene was dropped in [49.62 g (250.42 mmol, 6.3 eq.)
1-(3-chloropropyl)piperidine hydrochloride were dissolved in 262 ml of 1
M aq. NaOH solution and extracted with toluene (200 ml). The organic
phase was dried over Na2SO4]. The reaction was warmed up to RT
and stirred overnight. After 2 h at 50° C. and cooling to RT, the
reaction was neutralized with water (50 ml), evaporated and then
dissolved in sat. aq. NaHCO3/Et2O. After reextraction with
Et2O, the organic phase was dried (Na2SO4), evaporated and
crystallized from pentane to yield 12.08 g (90%) of the title compound as
white crystals. MS: 340.2 (MH.sup.+).

B) 4-(3-Piperidin-1-yl-propyl)-[1,4]diazepan-5-one; dihydrochloride

[0326]A solution of 7.3 g (21.50 mmol) of
5-oxo-4-(3-piperidin-1-yl-propyl)-[1,4]diazepane-1-carboxylic acid
tert-butyl ester was dissolved in 140 ml CH2Cl2, cooled to
0° C. and treated with 54 ml (215.03 mmol) of 4 M HCl in dioxane,
then warmed to After 3 h, 40 ml of MeOH were added to dissolve the
precipitation and stirring was continued over night. The solution was
evaporated, dissolved in toluene and evaporated (2×) to yield 7.71
g (quantitative) of the title compound as a white solid. MS: 240.1
(MH.sup.+).

Intermediate 7

(R)-2-Antino-4-benzyloxy-butyric Acid methyl ester; hydrochloride

[0327]In analogy to the procedure described for intermediate 5,
O-benzyl-D-homoserine gave the title compound in quantitative yield as
white solid. MS: 224.2 (MH.sup.+).

Intermediate 8

4-Methyl-piperidin-4-ol

[0328]Prepared according to the procedure published in J. Med. Chem. 1965,
8, 766-776.

[0330]To a solution of dimethylamine (0.91 ml, 7.18 mmol; 40% solution in
water) and 2.75 ml (19.76 mmol) of Et3N in 6 ml of CH2Cl2
cooled at 0° C. was added dropwise a solution of
2,5-dibromo-pentanoyl chloride (1.00 g, 3.59 mmol) in 4 ml
CH2Cl2. After stirring 1 h at RT, the reaction mixture was
partitioned between CH2Cl2 and water. The organic phases were
washed with water and brine and the aqueous layers extracted twice with
CH2Cl2. The organic phases were dried over MgSO4,
evaporated and purified by flash silica gel column (EtOAc/n-heptane 1:1)
to afford 0.66 g (64%) of the title product as light yellow oil. MS:
288.1 (2Br, MH.sup.+).

[0331]The title compound was produced in analogy to intermediate 1A from
methyl 4-(tert-butyldiphenylsilyloxy)-2-hydroxybutanoate (synthesized
from DL-malic acid as described in J. Org. Chem. 1993, 58, 7768). Orange
oil, MS: 468.2 (M+NH4).sup.+.

[0336]A mixture of 3,4-dichloroiodobenzene (1.50 g, 5.50 mmol), L-alanine
(734 mg, 8.25 mmol), copper(I) iodide, 2-hydroxybenzaldehyde
phenylhydrazone (233 mg, 1.10 mmol), tri-potassium phosphate (3.50 g,
16.5 mmol), and N,N-dimethylformamide (8 mL) was stirred at 80° C.
for 40 h, then after cooling diluted with water and acidified to pH 3 by
addition of 37% aq. HCl solution. The mixture was extracted with EtOAc,
the organic phase was washed with brine, dried (MgSO4), filtered,
and evaporated. Chromatography (SiO2; EtOAc) afforded the title
compound (1.08 g, 67%) as a 71:29 mixture of the (S) and (R)
stereoisomers (accordingly, when D-alanine was used instead of L-alanine
as starting material, the title compound was obtained as a 29:71 mixture
of the (S) and (R) stereoisomers). Brown solid, MS: 232.1 (M-H).sup.-.

Intermediate 12

2-(4-Chloro-3-trifluoromethyl-phenylamino)-propionic Acid

[0337]The title compound was produced in analogy with intermediate 11 from
2-chloro-5-iodobenzotrifluoride and L-alanine as a 80:20 mixture of the
(S) and (R) stereoisomers. Dark brown oil, MS: 266.2 (M-H).sup.-.

Intermediate 13

2-(4-Fluoro-3-trifluoromethyl-phenylamino)-propionic Acid

[0338]The title compound was produced in analogy with intermediate 11 from
2-fluoro-5-iodobenzotrifluoride and L-alanine as a 82:18 mixture of the
(S) and (R) stereoisomers. Dark brown oil, MS: 250.1 (M-H).sup.-.

Intermediate 14

2-(3-Chloro-4-fluoro-phenylamino)-propionic Acid

[0339]The title compound was produced in analogy with intermediate 11 from
3-chloro-4-fluoroiodobenzene and L-alanine as a 82:18 mixture of the (S)
and (R) stereoisomers. Brown solid, MS: 216.2 (M-H).sup.-.

Intermediate 15

2-(Biphenyl-4-ylamino)-propionic Acid

[0340]The title compound was produced in analogy with intermediate 11 from
4-bromo-biphenyl and L-alanine as a 82:18 mixture of the (S) and (R)
stereoisomers. Light yellow solid, MS: 240.3 (M-H).sup.-.

Intermediate 16

2-(Naphthalen-2-ylamino)-propionic Acid

[0341]The title compound was produced in analogy with intermediate 11 from
2-bromonaphthalene and L-alanine as a 66:34 mixture of the (S) and (R)
stereoisomers. Brown solid.

Intermediate 17

2-(3-Chloro-4-trifluoromethyl-phenylamino)-propionic Acid

[0342]The title compound was produced in analogy with intermediate 11 from
3-chloro-4-(trifluoromethyl)aniline and ethyl 2-bromopropionate, followed
by hydrolysis of the ester intermediate. Light yellow solid, MS: 266.2
(M-H).sup.-.

Intermediate 18

(S)-2-(3-Chloro-4-trifluoromethyl-phenylamino)-propionic Acid

[0343]A solution of (R)-(+)-1-phenylethylamine (104 mg, 0.86 mmol) in
diisopropyl ether/MeOH 20:1 (4.5 mL) was added dropwise at RT to a
solution of 2-(3-chloro-4-trifluoromethyl-phenylamino)-propionic acid
(417 mg, 1.56 mmol) in diisopropyl ether/MeOH 20:1 (4.5 mL), then after 2
h the precipitate was collected by filtration, washed with diisopropyl
ether, and dried under vacuum. This material was digested in chloroform
(3 mL) at 50° C. for 18 h, then collected by filtration, and dried
under vacuum to afford
2-(3-chloro-4-trifluoromethyl-phenylamino)-propionic acid
(R)-(+)-1-phenylethylamine salt (187 mg). This salt was partitioned
between 10% aq. KHSO4 solution and EtOAc. The organic layer was
dried (MgSO4), filtered, and evaporated to afford the title compound
(134 mg, 32%) in an enantiomeric ratio of 98.5:1.5. White solid.

Intermediate 19

(S)-2-(4-Chloro-3-trifluoromethoxy-phenylamino)-propionic Acid

A) 2-Chloro-4-iodo-1-trifluoromethyl-benzene

[0344]To a solution of 3-chloro-4-(trifluoromethyl)aniline (450 mg, 2.30
mmol) and toluene 4-sulfonic acid (1.19 g, 6.92 mmol) in CH3CN (10
mL) was added a solution of potassium iodide (955 mg, 5.76 mmol) and
sodium nitrite (318 mg, 4.61 mmol) in water (1.8 mL) over 15 min at
10° C., then after 20 min the reaction mixture was poured onto
water, neutralized with sat. aq. NaHCO3 solution, treated with 2 M
aq. sodium thiosulfate solution (6 mL), and extracted with EtOAc. The
organic layer was dried (MgSO4), filtered, and evaporated to afford
the title compound (517 mg) as a light brown oil, which was directly used
in the next step.

B) 2-(4-Chloro-3-trifluoromethoxy-phenylamino)-propionic Acid

[0345]The title compound was produced in analogy with intermediate 11 from
2-chloro-4-iodo-1-trifluoromethyl-benzene and L-alanine as a 70:30
mixture of the (S) and (R) stereoisomers. Yellow solid, MS: 282.3
(M-H).sup.-.

C) (S)-2-(4-Chloro-3-trifluoromethoxy-phenylamino)-propionic Acid

[0346]The title compound was produced in analogy with intermediate 18 from
2-(4-chloro-3-trifluoromethoxy-phenylamino)-propionic acid by fractional
crystallization with (R)-(+)-1-phenylethylamine and obtained in an
enantiomeric ratio of 99:1. White solid, MS: 282.2 (M-H).sup.-.

Intermediate 20

N-(3,4-Dichlorophenyl)glycine

[0347]The title compound was produced in analogy with intermediate 11 from
3,4-dichloroaniline and ethyl bromoacetate, followed by hydrolysis of the
ester intermediate. Off-white solid.

Intermediate 21

2-(4-Fluoro-3-trifluoromethoxy-phenylamino)-propionic Acid

[0348]The title compound was produced in analogy with intermediate 11 from
4-fluoro-3-(trifluoromethoxy)aniline and ethyl 2-bromopropionate,
followed by hydrolysis of the ester intermediate. Off-white solid, MS:
266.3 (M-H).sup.-.

Intermediate 22

2-(3,4-Dichloro-phenylamino)-butyric Acid

[0349]The title compound was produced in analogy with intermediate 11 from
3,4-dichloroaniline and ethyl 2-bromobutyrate, followed by hydrolysis of
the ester intermediate. Light yellow solid, MS: 246.3 (M-H).sup.-.

Intermediate 23

2-(3-Iodo-phenylamino)-propionic Acid

[0350]The title compound was produced in analogy with intermediate 11 from
3-iodoaniline and ethyl 2-bromopropionate, followed by hydrolysis of the
ester intermediate. Off-white solid, MS: 290.1 (M-H).sup.-.

Intermediate 24

(S)-2-(3,4-Dichloro-phenylamino)-propionic Acid

[0351]The title compound was produced in analogy with intermediate 18 from
2-(3,4-dichloro-phenylamino)-propionic acid (intermediate 11) by
fractional crystallization with (R)-(+)-1-phenylethylamine and obtained
in an enantiomeric ratio of 98:2. White solid, MS: 232.1 (M-H).sup.-.

Intermediate 25

(S)-2-(3-Trifluoromethoxy-phenylamino)-propionic Acid

A) 2-(3-Trifluoromethoxy-phenylamino)-propionic Acid

[0352]The title compound was produced in analogy with intermediate 11 from
3-(trifluoro-methoxy)aniline and ethyl 2-bromopropionate, followed by
hydrolysis of the ester intermediate. Light yellow solid, MS: 248.2
(M-H).sup.-.

B) (S)-2-(3-Trifluoromethoxy-phenylamino)-propionic Acid

[0353]The title compound was produced in analogy with intermediate 18 from
2-(3-trifluoromethoxy-phenylamino)-propionic acid by fractional
crystallization with (R)-(+)-1-phenylethylamine and obtained in an
enantiomeric ratio of 96:4. Light yellow solid, MS: 248.2 (M-H).sup.-.

Intermediate 26

2-(4-Trifluoromethyl-phenylamino)-propionic Acid

[0354]The title compound was produced in analogy with intermediate 11 from
4-(trifluoro-methyl)aniline and ethyl 2-bromopropionate, followed by
hydrolysis of the ester intermediate. Light brown solid, MS: 232.1
(M-H).sup.-.

Intermediate 27

2-(3-Fluoro-4-trifluoromethyl-phenylamino)-propionic Acid

[0355]The title compound was produced in analogy with intermediate 11 from
3-fluoro-4-(trifluoromethyl)aniline and ethyl 2-bromopropionate, followed
by hydrolysis of the ester intermediate. Light yellow solid.

[0365]In analogy to the procedure described for example 1D,
(S)-2-[4-(3,4-dichloro-phenyl)-7-oxo-[1,4]diazepan-1-yl]-4-hydroxy-butyri-
c acid methyl ester gave the title compound in 97% yield as orange foam.
MS: 373.1 (MH.sup.+, 2Cl).

[0371]In analogy to the procedure described in example 1E to 1G,
3-[(3-chloro-phenyl)-(2-oxo-ethyl)-amino]-propionic acid tert-butyl ester
gave the title compound as off-white gum. MS: 431.3 (MH.sup.+, 1Cl).

[0372]In analogy to the procedure described in example 1H and 1I,
(S)-4-benzyloxy-2-[4-(3-chloro-phenyl)-7-oxo-[1,4]diazepan-1-yl]-butyric
acid methyl ester gave the title compound as orange oil. MS: 339.1
(MH.sup.+, 1Cl).

[0375]In analogy to the procedure described in example 2,
(S)-2-[4-(3-chloro-phenyl)-7-oxo-[1,4]diazepan-1-yl]-4-((S)-4-hydroxy-6-a-
za-spiro[2.5]oct-6-yl)-butyric acid methyl ester and LiBH4 gave the
title compound in 77% yield as a white foam. MS: 421.2 (MH.sup.+, 1Cl).

[0378]In analogy to the procedure described in example 1E to 1G,
3-[(2-oxo-ethyl)-(3-trifluoromethyl-phenyl)-amino]-propionic acid
tert-butyl ester gave the title compound as light yellow oil. MS: 465.2
(MH.sup.+).

[0379]A solution of 1.49 g (3.22 mmol) of
(S)-4-benzyloxy-2-[7-oxo-4-(3-trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-
-butyric acid methyl ester in 50 ml of MeOH was treated with a solution of
3.22 ml of 1 M aq. HCl solution and 0.15 g of palladium on activated
charcoal (10%) and was stirred over H2-atmosphere for 1.5 h. After
filtration, the solution was evaporated, dissolved in CH2Cl2
and washed with aq. sat. NaHCO3 solution (freshly prepared), dried
over Na2SO4 and evaporated under reduced pressure to yield 1.08
g (90%) of a mixture of
4-((S)-2-oxo-tetrahydro-furan-3-yl)-1-(3-trifluoromethyl-phenyl)-[1,4]dia-
zepan-5-one (ca 5-10%) and the title compound as white foam. MS: 375.2
(MH.sup.+).

[0380]In analogy to the procedure described in example 1I,
(S)-4-hydroxy-2-[7-oxo-4-(3-trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-b-
utyric acid methyl ester gave a mixture of
4-((S)-2-oxo-tetrahydro-furan-3-yl)-1-(3-trifluoromethyl-phenyl)-[1,4]dia-
zepan-5-one (ca 5-10%) and the title compound in 97% yield as orange oil.
MS: 373.1 (MH.sup.+).

[0383]In analogy to the procedure described in example 2,
(S)-4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-2-[7-oxo-4-(3-trifluoromet-
hyl-phenyl)-[1,4]diazepan-1-yl]-butyric acid methyl ester and LiBH4
gave the title compound in 64% yield as a white foam. MS: 456.4
(MH.sup.+).

[0388]In analogy to the procedure described in example 1F and 1G,
(R)-4-benzyloxy-2-{2-[(2-tert-butoxycarbonyl-ethyl)-(3-trifluoromethyl-ph-
enyl)-amino]-ethylamino}-butyric acid methyl ester gave the title compound
as light yellow oil. MS: 465.2 (MH.sup.+).

[0389]In analogy to the procedure described in example 5C,
(R)-4-benzyloxy-2-[7-oxo-4-(3-trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-
-butyric acid methyl ester was hydrogenated to give the title compound in
97% yield as white oil. MS: 375.2 (MH.sup.+).

[0390]In analogy to the procedure described in example 1I,
(R)-4-hydroxy-2-[7-oxo-4-(3-trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-b-
utyric acid methyl ester gave the title compound in quantitative yield as
orange oil. MS: 373.1 (MH.sup.+).

[0391]In analogy to the procedure described in example 1K,
(R)-4-oxo-2-[7-oxo-4-(3-trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-butyr-
ic acid methyl ester and (S)-6-aza-spiro[2.5]octan-4-ol; hydrochloride
(intermediate 2) gave the title compound in 77% as white foam. MS: 484.4
(MH.sup.+).

[0393]In analogy to the procedure described in example 2,
(R)-4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-2-[7-oxo-4-(3-trifluoromet-
hyl-phenyl)-[1,4]diazepan-1-yl]-butyric acid methyl ester and LiBH4
gave the title compound in 60% yield as a white foam. MS: 456.4
(MH.sup.+).

[0396]In analogy to the procedure described in example 1I,
(S)-4-hydroxy-2-(7-oxo-4-phenyl-[1,4]diazepan-1-yl)-butyric acid methyl
ester gave the title compound in quantitative yield as light brown gum.
MS: 305.2 (MH.sup.+).

[0397]In analogy to the procedure described in example 1K,
(S)-4-oxo-2-(7-oxo-4-phenyl-[1,4]diazepan-1-yl)-butyric acid methyl ester
and (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2) gave
the title compound in 50% as light yellow foam. MS: 416.3 (MH.sup.+).

[0400]In analogy to the procedure described in example 1E to 1G,
3-[(2-oxo-ethyl)-(4-trifluoromethoxy-phenyl)-amino]-propionic acid
tert-butyl ester gave the title compound as light yellow oil. MS: 481.3
(MH.sup.+).

[0401]In analogy to the procedure described in example 5C,
(S)-4-benzyloxy-2-[7-oxo-4-(4-trifluoromethoxy-phenyl)-[1,4]diazepan-1-yl-
]-butyric acid methyl ester was hydrogenated to give the title compound in
98% yield as white oil. MS: 391.0 (MH.sup.+).

[0402]In analogy to the procedure described in example 1I,
(S)-4-hydroxy-2-[7-oxo-4-(4-trifluoromethoxy-phenyl)-[1,4]diazepan-1-yl]--
butyric acid methyl ester gave the title compound in quantitative yield as
brown oil. MS: 389.1 (MH.sup.+).

[0405]In analogy to the procedure described in example 2,
(S)-4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-2-[7-oxo-4-(4-trifluoromet-
hoxy-phenyl)-[1,4]diazepan-1-yl]-butyric acid methyl ester and LiBH4
gave the title compound in 79% yield as a white foam. MS: 472.3
(MH.sup.+).

[0408]In analogy to the procedure described in example 1E to 1G,
3-[(2-oxo-ethyl)-(3-trifluoromethoxy-phenyl)-amino]-propionic acid
tert-butyl ester gave the title compound as light brown oil. MS: 481.3
(MH.sup.+).

[0409]In analogy to the procedure described in example 5C,
(S)-4-benzyloxy-2-[7-oxo-4-(3-trifluoromethoxy-phenyl)-[1,4]diazepan-1-yl-
]-butyric acid methyl ester was hydrogenated to give the title compound in
98% yield as white foam. MS: 391.1 (MH.sup.+).

[0410]In analogy to the procedure described in example 1I,
(S)-4-hydroxy-2-[7-oxo-4-(3-trifluoromethoxy-phenyl)-[1,4]diazepan-1-yl]--
butyric acid methyl ester gave the title compound in 98% yield as light
red oil. MS: 389.1 (MH.sup.+).

[0413]In analogy to the procedure described in example 2,
(S)-4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-2-[7-oxo-4-(3-trifluoromet-
hoxy-phenyl)-[1,4]diazepan-1-yl]-butyric acid methyl ester and LiBH4
gave the title compound in 73% yield as a white foam. MS: 472.3
(MH.sup.+).

[0415]A mixture of 5.00 g (43.80 mmol) 1,4-diazepan-5-one, 16.64 g (87.61
mmol) of 3-(trifluoromethylphenyl)boronic acid, 11.94 g (65.70 mmol) of
copper(II) acetate and 10 spoonful of molecular sieves (0.4 nm) were
degassed (Argon) and the treated with 6.93 ml (87.61 mmol) of pyridine in
200 ml of CH2Cl2. The blue suspension became slowly green
during stirring for 4 days. The mixture was filtered and evaporated. The
residue was taken up in EtOAc and washed with sat. aq NaHCO3
solution (4×) and dried over Na2SO4. After evaporation
and purification by flash silica gel column (n-heptane:EtOAc gradient,
then EtOAc:MeOH 95:5), 0.997 g (9%) of the title compound as light brown
solid were received. MS: 258.9 (MH.sup.+).

[0416]A solution of 1.60 g (1.94 mmol) of
1-(3-trifluoromethyl-phenyl)-[1,4]diazepan-5-one in 15 ml of DMF was
treated at 0° C. with 0.33 g (7.44 mmol) of NaH (55% dispersion in
oil). After 20 min at this temperature, the suspension was warmed to RT
and added to a cooled solution (0° C.) of 2.33 g (6.50 mmol) of
(rac)-4-(tert-butyl-dimethyl-silanyloxy)-2-iodo-butyric acid methyl ester
(intermediate 1) in 15 ml of DMF. The solution was stirred 6 h at
0° C. and neutralized with cold 10% aq.KH2PO4 solution
and extracted with Et2O (3×). The organic phases were washed
with 10% aq.KH2PO4 solution, dried over Na2SO4
evaporated and purified by flash silica gel column
(CH2Cl2:Et2O 4:1 to 2:1) to yield 2.06 g (68%) of the
title compound as light yellow oil. MS: 489.2 (MH.sup.+)

[0417]A solution of 1.03 g (2.12 mmol) of
(rac)-4-(tert-butyl-dimethyl-silanyloxy)-2-[7-oxo-4-(3-trifluoromethyl-ph-
enyl)-[1,4]diazepan-1-yl]-butyric acid methyl ester in 6 ml of
CH2Cl2 was treated at 0° C. with 2.33 ml (2.33 mmol, 1M
in CH2Cl2) of boron tribromide and kept 2.5 h at this
temperature. The solution was warmed to RT cooled (0° C.) and
treated again with 2.33 ml (2.33 mmol, 1M in CH2Cl2) of boron
tribromide. After 1 h at this temperature, the reaction was extracted
with cold sat. aq. NaHCO3 and EtOAc solution (3×). The organic
phases were washed with sat. aq. NaHCO3solution, dried over
Na2SO4 and evaporated to give 1.14 g of the crude compound.
Purification by flash silica gel column ((n-heptane:EtOAc 95:5, 1:1 to
EtOAc) gave 0.086 g (11%) of the title compound as light yellow oil, MS:
437.1 (MH.sup.+, 1Br) and

[0421]In analogy to the procedure described in example 2,
(R,S)-4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-2-[7-oxo-4-(3-trifluorom-
ethyl-phenyl)-[1,4]diazepan-1-yl]-butyric acid methyl ester and LiBH4
gave the title compound in 50% yield as off-white foam. MS: 456.4
(MH.sup.+).

[0423]0.26 g (0.76 mmol) of
(rac)-4-(2-oxo-tetrahydro-furan-3-yl)-1-(3-trifluoromethyl-phenyl)-[1,4]d-
iazepan-5-one (example 15C) was dissolved in 3 ml of EtOH and treated with
2.71 ml (15.19 mmol) of a solution of dimethylamine (5.6 M in EtOH). The
reaction was stirred 20 h at RT, evaporated and re-evaporated with
toluene to afford 0.31 g (quantitative) of the title compound as yellow
oil. MS: 388.1 (MH.sup.+).

[0424]In analogy to the procedure described in example 1D,
(rac)-4-hydroxy-N,N-dimethyl-2-[7-oxo-4-(3-trifluoromethyl-phenyl)-[1,4]d-
iazepan-1-yl]-butyramide gave the title compound in 90% yield as an yellow
gum. MS: 349.2 (MH.sup.+).

[0425]In analogy to the procedure described in example 1E,
(rac)-N,N-dimethyl-4-oxo-2-[7-oxo-4-(3-trifluoromethyl-phenyl)-[1,4]diaze-
pan-1-yl]-butyramide and (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride
(intermediate 2) gave the title compound in 67% yield as white foam. MS:
497.3 (MH.sup.+).

[0427]In analogy to the procedure described in example 1E,
(rac)-N,N-dimethyl-4-oxo-2-[7-oxo-4-(3-trifluoromethyl-phenyl)-[1,4]diaze-
pan-1-yl]-butyramide (example 17B) and (3S,5S)-5-methyl-piperidin-3-ol;
hydrochloride (intermediate 4) gave the title compound in 60% yield as
off-white foam. MS: 485.3 (MH.sup.+).

[0430]In analogy to the procedure described in example 1E to 1G,
3-[(2-oxo-ethyl)-(4-trifluoromethyl-phenyl)-amino]-propionic acid
tert-butyl ester gave the title compound as white oil. MS: 465.2
(MH.sup.+).

[0431]In analogy to the procedure described in example 5C,
(S)-4-benzyloxy-2-[7-oxo-4-(4-trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-
-butyric acid methyl ester was hydrogenated to give the title compound in
94% yield as white foam. MS: 375.2 (MH.sup.+).

[0432]In analogy to the procedure described in example 11,
(S)-4-hydroxy-2-[7-oxo-4-(4-trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-b-
utyric acid methyl ester gave the title compound in quantitative yield as
yellow oil. MS: 373.1 (MH.sup.+).

[0435]In analogy to the procedure described in example 2,
(S)-4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-2-[7-oxo-4-(4-trifluoromet-
hyl-phenyl)-[1,4]diazepan-1-yl]-butyric acid methyl ester and LiBH4
gave the title compound in 75% yield as a white foam. MS: 456.3
(MH.sup.+).

[0438]0.105 g (0.22 mmol) of Lithium;
(R)-4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-2-[7-oxo-4-(3-trifluoromet-
hyl-phenyl)-[1,4]diazepan-1-yl]-butyrate was dissolved at RT in 1.2 ml of
DMF followed by addition of 0.020 g (0.24 mmol) dimethylamine
hydrochloride, 0.123 ml (0.88 mmol) of triethylamine and at 0° C.
with 0.095 g (0.24 mmol) of HATU. The solution was stirred overnight and
warmed up to RT. The reaction was poured on a sat. aq. NaHCO3
solution followed by extraction with EtOAc (3 times). The organic phases
were washed with a solution of sat. aq. NaHCO3 solution and with a
solution of NaCl 10%. The combined organic phases were dried over
Na2SO4 and the solvent was removed under vacuum. The crude
product was purified by flash chromatography (20 g amine-silica,
AcOEt/n-heptane 9:1) to yield 0.095 g (87%) of the title compound as a
white foam. MS: 497.3 (MH.sup.+).

[0440]In analogy to the procedure described in example 17A,
4-((S)-2-oxo-tetrahydro-furan-3-yl)-1-(3-trifluoromethyl-phenyl)-[1,4]dia-
zepan-5-one (example 7) and dimethylamine (5.6 M in EtOH) gave the title
compound in quantitative yield as an yellow oil. MS: 388.1 (MH.sup.+).

[0441]In analogy to the procedure described in example 11,
(S)-4-hydroxy-N,N-dimethyl-2-[7-oxo-4-(3-trifluoromethyl-phenyl)-[1,4]dia-
zepan-1-yl]-butyramide gave the title compound in 99% yield as yellow oil.
MS: 386.1 (MH.sup.+).

[0442]In analogy to the procedure described in example 1K,
(S)-N,N-dimethyl-4-oxo-2-[7-oxo-4-(3-trifluoromethyl-phenyl)-[1,4]diazepa-
n-1-yl]-butyramide and (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride
(intermediate 2) gave the title compound in 57% yield as white foam. MS:
497.3 (MH.sup.+).

[0446]In analogy to the procedure described in example 5C,
4-((S)-3-benzyloxy-1-methoxymethyl-propyl)-1-(3-trifluoromethyl-phenyl)-[-
1,4]diazepan-5-one was hydrogenated to give the title compound in 92%
yield as off-white gum. MS: 361.1 (MH.sup.+).

[0447]In analogy to the procedure described in example 1I,
4-((S)-3-hydroxy-1-methoxymethyl-propyl)-1-(3-trifluoromethyl-phenyl)-[1,-
4]diazepan-5-one gave the title compound in 91% yield as light yellow oil.
MS: 359.2 (MH.sup.+).

[0448]In analogy to the procedure described in example 1K,
(S)-4-methoxy-3-[7-oxo-4-(3-trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-b-
utyraldehyde and (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride
(intermediate 2) gave the title compound in 58% yield as light yellow
foam. MS: 470.2 (MH.sup.+).

[0458]In analogy to the procedure described in example 2,
(R,S)-5-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-2-[7-oxo-4-(3-trifluorom-
ethyl-phenyl)-[1,4]diazepan-1-yl]-pentanoic acid methyl ester (example 26)
was treated with LiBH4 to give the title compound in 73% yield as
white foam. MS: 470.2 (MH.sup.+).

[0460]In analogy to the procedure described in example 23B,
4-[(R,S)-4-((S)-4-hydroxy-6-aza-spiro
[2.5]oct-6-yl)-1-hydroxymethyl-butyl]-1-(3-trifluoromethyl-phenyl)-[1,4]d-
iazepan-5-one (example 27) was treated with iodomethane and NaH to give
the title compound in 21% yield as colorless oil. MS: 484.4 (MH.sup.+).

[0464]In analogy to the procedure described in example 2, the reduction of
(rac)-5-(4-hydroxy-4-methyl-piperidin-1-yl)-2-[7-oxo-4-(3-trifluoromethyl-
-phenyl)-[1,4]diazepan-1-yl]-pentanoic acid methyl ester with SBH gave the
title compound in 98% yield as white foam. MS: 458.3 (MH.sup.+).

[0466]In analogy to the procedure described in example 23B,
(rac)-4-[1-hydroxymethyl-4-(4-hydroxy-4-methyl-piperidin-1-yl)-butyl]-1-(-
3-trifluoromethyl-phenyl)-[1,4]diazepan-5-one was treated with iodomethane
and NaH to give the title compound in 25% yield as colorless oil. MS:
472.4 (MH.sup.+).

[0469]In analogy to the procedure described in example 15B,
1-(3-trifluoromethoxy-phenyl)-[1,4]diazepan-5-one and
(rac)-2,5-dibromo-pentanoic acid methyl ester gave the title compound in
92% yield as colorless oil. MS: 469.1 (1Br, MH.sup.+).

[0471]In analogy to the procedure described in example 2,
(R,S)-5-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-2-[7-oxo-4-(3-trifluorom-
ethoxy-phenyl)-[1,4]diazepan-1-yl]-pentanoic acid methyl ester was treated
with LiBH4 to give the title compound in 92% yield as white foam.
MS: 486.3 (MH.sup.+).

[0473]A solution of 8.52 g (39.75 mmol) of
5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester in 200 ml of DMA
was treated at 0° C. with 2.60 g (59.62 mmol) of NaH (55%
dispersion in oil) in small portions. The reaction was stirred 1 h at
this temperature, then the free 1-(3-chloropropyl)piperidine in 200 ml
toluene was dropped in [49.62 g (250.42 mmol, 6.3 eq.)
1-(3-chloropropyl)piperidine hydrochloride were dissolved in 262 ml of 1
M aq. 1N NaOH solution and extracted with toluene (200 ml). The organic
phase was dried over Na2SO4]. The reaction was warmed up to RT
and stirred over night. After 2 h at 50° C. and cooling to RT, the
reaction was neutralized with water (50 ml), evaporated and then
dissolved in aq. sat. NaHCO3 solution/Et2O. After reextraction
with Et2O, the organic phase was dried (Na2SO4),
evaporated and crystallized from pentane to yield 12.08 g (90%) of the
title compound as white crystals. MS: 340.2 (MH.sup.+).

B) 4-(3-Piperidin-1-yl-propyl)-[1,4]diazepan-5-one

[0474]A solution of 7.3 g (21.50 mmol) of
5-oxo-4-(3-piperidin-1-yl-propyl)-[1,4]diazepane-1-carboxylic acid
tert-butyl ester was in 140 ml CH2Cl2, cooled to 0° C.
and treated with 54 ml (215 mmol) of HCl solution (4 M dioxane), then
warmed to RT. After 3 h, 40 ml of MeOH were added to dissolve the
precipitation and stirring was continued over night. The solution was
evaporated, dissolved in aq. sat. NaHCO3. solution, the water
evaporated and the solid extracted with in CH2Cl2:MeOH 9:1.
Concentration afforded the title compound 5.0 g (97%) as yellow oil. MS:
240.1 (MH.sup.+).

[0489]To a cooled (-78° C.) solution of
4-[2-(methoxy-methyl-carbamoyl)-ethyl]-5-oxo-[1,4]diazepane-1-carboxylic
acid tert-butyl ester 3 g (9 mmol) was added dropwise a solution of
lithium aluminum hydride 9.1 ml (9 mmol, 1 M solution in THF). The
mixture was quenched by addition of acetone and then AcOH. The reaction
was allowed to reach RT after which time water and 10% aq. KHSO4
solution were added and the mixture repeatedly extracted with TBME. The
combined organic was washed with brine, dried (MgSO4) and
concentrated. Purification by flash column chromatography (EtOAc:MeOH
19:1) afforded the title compound 1.5 g (61%) as a colorless oil. MS:
271.5 (MH.sup.+).

[0490]To a suspension of (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride
(intermediate 2) 0.16 g (1 mmol) in CH2Cl2 (5 ml) was added
Et3N 0.14 ml (1 mmol) and AcOH 0.11 ml (2 mmol) followed by a
solution of 5-oxo-4-(3-oxo-propyl)-[1,4]diazepane-1-carboxylic acid
tert-butyl ester 0.34 g (1 mmol) in CH2Cl2 (5 ml) and finally
sodium triacetoxyborohydride 0.25 g (1 mmol). The mixture was stirred for
1 h after which time sat. aq.NaHCO3. solution was added, the
reaction extracted with in CH2Cl2, dried (Na2SO4) and
concentrated. The residue was taken up in 1 M HCl solution in dioxane (10
ml), stirred for 10 minutes before the solvent was evaporated. The
residue was then dissolved in sat. aq. NaHCO3. solution the water
removed by evaporation, and the solid extracted with
CH2Cl2:MeOH (9:1). Concentration afforded the title compound
0.2 g (71%) as yellow oil. MS: 282.1 (MH.sup.+).

[0491]The title compound was prepared from
4-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-[1,4]diazepan-5-one
and 1-iodo-3-trifluoromethoxy-benzene in analogy to example 33. MS: 442.3
(MH.sup.+).

[0493]2.0 g (14 mmol) of (R)-propane-1,2-diamine dihydrochloride were
charged in the reactor followed by MeOH/H2O (4/1 10 ml). To the
resulting solution was added in one portion a solution of 3.8 g (17 mmol)
of di-tert-butyl dicarbonate dissolved in MeOH (2 ml). The reaction was
cooled to 5° C. 4.4 ml (18 mmol) of aq. 4 M NaOH solution were
added dropwise over 2 h. The reaction was allowed to warm to RT. After 17
h, the organic solvents were removed under reduced pressure. 25 ml of
EtOAc and 25 ml of water were added. The aqueous phase was adjusted to pH
2-3 with 1 M aq. HCl solution (ca 2 ml). The aqueous phase was separated
and washed with 25 ml EtOAc. The organic phases were combined and water
(25 ml) was added. The pH was adjusted to pH 2-3 (with 0.5 ml 1 M aq. HCl
solution), the organic phase was separated and discarded. The aqueous
phases were combined, adjusted to pH 14 by adding ca 2 ml aq NaOH 32%
solution and extracted twice with 50 ml CH2Cl2. The organic
phases were combined, dried (MgSO4), filtered and concentrated under
reduced to afford 1.6 g of the title product as a colorless oil (67%
yield, 97% regioselectivity by GC). MS: 175.2 (MH.sup.+).

[0510]NaH (55% dispersion in mineral oil, 24 mg, 0.56 mmol) was added at
0° C. to a solution of
3-methyl-4-(3-trifluoromethoxy-phenyl)-piperazin-2-one (example 41D; 127
mg, 0.46 mmol) in N,N-dimethylformamide (3 mL), then after 5 min a
solution of 3-bromo-N-methoxy-N-methyl-propionamide (Patent Application
US 2007249589; 100 mg, 0.51 mmol) was added. After 30 min the ice bath
was removed and the reaction mixture was allowed to reach RT over 1 h,
then partitioned between EtOAc and 10% aq. KHSO4 solution. The
organic layer was washed with brine, dried (MgSO4), filtered, and
evaporated to afford the title compound (189 mg) which was directly used
in the next step. Light yellow oil, MS: 390.3 (M+H).sup.+.

[0544]The title compound was produced in analogy to example 41E from
3-methyl-4-(3-trifluoromethyl-phenyl)-piperazin-2-one (example 51D) and
4-benzyl-2-(chloromethyl)morpholine. Yellow oil, MS: 448.2 (M+H).sup.+.

[0546]The title compound was produced in analogy to example 41E from
3-methyl-4-(3-trifluoromethyl-phenyl)-piperazin-2-one (example 51D) and
3-chloromethyl-1-methylpiperidine. Yellow oil, MS: 370.2 (M+H).sup.+.

[0549]0.080 g (0.17 mmol) of lithium;
(S)-2-[4-(3,4-dichloro-phenyl)-7-oxo-[1,4]diazepan-1-yl]-4-((S)-4-hydroxy-
-6-aza-spiro[2.5]oct-6-yl)-butyrate was dissolved at RT in 0.88 ml of
N,N-dimethylformamide followed by addition of 0.094 ml (0.67 mmol, 4 eq.)
of triethylamine, 0.015 g (0.18 mmol, 1.1 eq.) of dimethylamine
hydrochloride and at 0° C. with 0.072 g (0.18 mmol, 1.1 eq.) of
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate. The solution was stirred overnight and warmed up to
RT. The reaction was poured on a solution of sat. aq. NaHCO3
solution, followed by extraction with EtOAc (3 times). The organic phases
were washed with a solution of sat. aq. NaHCO3 solution and with 10%
aq. NaCl solution. The combined organic phases were dried over
Na2SO4 and the solvent was removed under vacuum. The crude
product was purified by flash chromatography (20 g IST Isolute® Flash
NH2; EtOAc/n-heptane 9: 1) to give 0.072 g (86%) of the title
compound as white foam. MS: 497.3 (MH.sup.+, 2Cl).

[0553]In analogy to the procedure described in example 59B, lithium;
(S)-2-[4-(3,4-dichloro-phenyl)-7-oxo-[1,4]diazepan-1-yl]-4-((S)-4-hydroxy-
-6-aza-spiro[2.5]oct-6-yl)-butyrate (example 59A) and
2-methylamino-ethanol (but with 1 eq. of triethylamine) gave 0.060 g
(68%) of the title compound as white foam. MS: 527.3 (MH.sup.+, 2Cl).

[0555]0.080 g (0.17 mmol) of lithium;
(S)-2-[4-(3,4-dichloro-phenyl)-7-oxo-[1,4]diazepan-1-yl]-4-((S)-4-hydroxy-
-6-aza-spiro[2.5]oct-6-yl)-butyrate (example 59A) and 0.021 g (0.18 mmol,
1.1 eq.) of N-hydroxy-2-pyridone were suspended in 4 ml CH2Cl2
and treated at 0° C. with 0.036 g (0.18 mmol, 1.1 eq.) of
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride. The cooling
bath was allowed to come to RT and the reaction mixture became cloudier.
After addition of 2.0 ml of N,N-dimethylformamide, this reaction mixture
went into solution. The solution was stirred overnight at RT. 0.031 g
(0.18 mmol, 1.1 eq.) of N-cyclopropylmethylamine oxalate salt was
dissolved in 1.5 ml of dimethyl sulfoxide, treated with 0.026 ml (0.18
mmol, 1.1 eq.) of triethylamine and added to the activated ester
intermediate. After 1 h at RT, the reaction was poured on a solution of
sat. aq. NaHCO3 solution and extracted with diethyl ether (3 times).
The organic phases were washed with a solution of sat. aq. NaHCO3
solution and with 10% aq. NaCl solution. The combined organic phases were
dried over Na2SO4 and the solvent was removed under vacuum. The
crude product was purified by flash chromatography (20 g IST Isolute®
Flash NH2; EtOAc/n-heptane 1:1, 2:1) to give 0.062 g (71%) of the
title compound as white foam. MS: 523.2 (MH.sup.+, 2Cl).

[0561]33.11 ml (33.11 mmol, 1 M in THF) of a borane-tetrahydrofuran
complex solution was added dropwise at 0° C. to a solution of 3.10
g (13.24 mmol) 2-(3,4-dichloro-phenylamino)-propionic acid (synthesized
in analogy to intermediate 11, with 3,4-dichloroiodobenzene, D-alanine
and copper(I) iodide, 2-hydroxybenzaldehyde phenylhydrazone and
tri-potassium phosphate in N,N-dimethylformamide; enantiomeric ratio
71:29) in 50 ml THF, then after 10 min the ice bath was removed and the
solution stirred for 2 h at RT. After cooling, 22 ml of MeOH and 1.1 ml
of H2SO4 were added, and after 30 min at RT and 1 h at reflux
the reaction mixture was concentrated in vacuo. The residue was
partitioned between NaCl sat. 1 M aq. sodium hydroxide solution and EtOAc
(3×). The organic layer was washed with brine, dried
(Na2SO4), filtered, and evaporated. Flash silica gel column
(CH2Cl2/MeOH 99:1→98:2) afforded 2.90 g (99%) of the
title compound as a 71:29 mixture of the (R) and (S) stereoisomers.
Yellow oil, MS: 220.0 (MH.sup.+, 2Cl)

[0562]To a solution of 0.73 ml (8.36 mmol) of oxalyl chloride in 21 ml
CH2Cl2 at -50 to -60° C. was added a solution of 1.24 ml
(17.45 mmol) dimethylsulfoxide in 5 ml of CH2Cl2 within 10 min.
The solution was stirred for 5 min and a solution of 1.600 (7.27 mmol)
2-(3,4-dichloro-phenylamino)-propan-1-ol in 21 ml of CH2Cl2 was
added within 10 min. The mixture was stirred for 15 min and 5.07 ml
(36.35 mmol) of triethylamine were added within 20 min. The suspension
was stirred for 75 min and slowly warmed to 0° C. (complete
oxidation followed by TLC, SiO2, EtOAc:n-heptane 1:1). 1.88 g (7.27
mmol) of (S)-2-amino-4-benzyloxy-butyric acid methyl ester hydrochloride
(intermediate 5) was added and 0.9 ml of acetic to adjust the pH to 5
followed by 1.75 g (8.00 mmol) of sodium triacetoxyborohydride. After 5
min at 0° C. and 1.5 h at RT, the reaction was poured on a
solution of sat. aq. NaHCO3 solution, followed by extraction with
EtOAc (3 times). The organic phases were washed with a solution of 10%
aq. NaCl solution. The combined organic phases were dried over
Na2SO4 and the solvent was removed under vacuum to give 3.13 g
(quantitative) of the title compound as a 71:29 mixture of the (R) and
(S) diastereomers. Yellow oil, MS: 425.2 (MH.sup.+, 2Cl).

[0563]A solution of 1.26 g (2.96 mmol) of
(S)-4-benzyloxy-2-[2-(3,4-dichloro-phenylamino)-propylamino]-butyric acid
methyl ester in 30 ml CH2Cl2 was treated with a solution of
0.91 g (3.55 mmol) of 2-chloro-1-methylpyridinium iodide and 0.48 g (3.55
mmol) of 3,3-dimethoxy-propionic acid (synthesized from methyl
3,3-dimethoxy-propionate by hydrolysis with LiOH) in 20 ml of
CH2Cl2. The suspension was cooled and treated at 0° C.
with 1.77 ml (7.41 mmol) of tributylamine. The cooling bath was removed
after 10 min and stirring was continued over night. The reaction was
extracted with 10% aq. KHSO4 solution/diethyl ether (3×). The
organic phases were washed with 10% aq. KHSO4 solution (2×),
sat. aq. NaHCO3 solution, 10% aq. NaCl solution and dried over
Na2SO4 to yield 1.53 g (96%) of the title compound as a 71:29
mixture of the (R) and (S) diastereomers. Yellow oil, MS: 541.2
(MH.sup.+, 2Cl).

[0565]In analogy to the procedure described in example 1H,
(S)-4-benzyloxy-2-[4-(3,4-dichloro-phenyl)-3-methyl-7-oxo-[1,4]diazepan-1-
-yl]-butyric acid methyl ester and boron tribromide (after warming up the
reaction to maximum to -5° C.) gave after precipitation
CH2Cl2/n-pentane 78% of the title compound as a 71:29 mixture
of the (R) and (S) diastereomers. Off-white foam, MS: 447.0 (M+OAc.sup.-,
2Cl).

[0566]In analogy to the procedure described in example 1D,
(S)-2-[4-(3,4-dichloro-phenyl)-3-methyl-7-oxo-[1,4]diazepan-1-yl]-4-hydro-
xy-butyric acid methyl ester gave the title compound in a yield of 87% as
a 71:29 mixture of the (R) and (S) diastereomers. Light brown foam, MS:
387.1 (MH.sup.+, 2Cl).

[0576]The title compound was produced in analogy with the procedure of
example 33A from
4-(4-chloro-3-trifluoromethyl-phenyl)-3-methyl-piperazin-2-one and
1-(3-chloropropyl)piperidine. Yellow viscous oil, MS: 418.3 (M+H).sup.+.

[0586]A mixture of (S)-6-(3-amino-propyl)-6-aza-spiro[2.5]octan-4-ol (200
mg, 1.09 mmol), bromoacetaldehyde (183 mg, 1.09 mmol), potassium
carbonate (300 mg, 2.17 mmol), and EtOH (2.5 mL) was heated at
150° C. for 20 min under microwave irradiation, then insoluble
material was removed by filtration and the filtrate evaporated to afford
224 mg of a 60:40 mixture of the title compound and the tertiary amine
(S)-6-{3-[bis-(2,2-dimethoxy-ethyl)-amino]-propyl}-6-aza-spiro[2.5]octan--
4-ol, which was directly used in the next step. Yellow gum, MS: 273.2
(M+H).sup.+.

[0615]The title compound was produced in analogy with examples 72/73 by
HPLC purification of the epimeric mixture,
4-(4-fluoro-3-trifluoromethoxy-phenyl)-1-[3-((S)-4-hydroxy-6-aza-spiro[2.-
5]oct-6-yl)-propyl]-3-methyl-piperazin-2-one. Yellow gum, MS: 460.3
(M+H).sup.+.

[0639]The title compound was produced in analogy with example 94, steps E
and F. Thus, (S)-2-(3-trifluoromethoxy-phenylamino)-propionic acid
(intermediate 25) was coupled in step E with
(2,2-dimethoxy-ethyl)-[4-((S)-4-triethylsilanyloxy-6-aza-spiro[2.5]oct-6--
yl)-butyl]-amine (example 94D), leading to
(S)-2-(3-trifluoromethoxy-phenylamino)-N-(2,2-dimethoxy-ethyl)-N-[4-((S)--
4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-butyl]-propionamide, which was
converted to the title compound in step F. Light yellow gum, MS: 456.4
(M+H).sup.+.

[0646]The title compound was produced in analogy with example 83C from
(R)-2-triethylsilanyloxy-3-((S)-4-triethylsilanyloxy-6-aza-spiro[2.5]oct--
6-yl)-propylamine. Colourless liquid, MS: 517.4 (M+H).sup.+.

[0657]The title compound was produced in analogy with example 94F from
N-(2,2-dimethoxy-ethyl)-2-(3-fluoro-4-trifluoromethyl-phenylamino)-N-[3-(-
(S)-4-triethylsilanyloxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-propionamide.
Light yellow gum.

[0669]The title compound was produced in analogy with example 104, steps
A-H. Thus, reaction of 2-allyl-oxirane with benzyl carbamate in the
presence of
(1R,2R)-(-)-N-N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamin-
ocobalt(II) in step A led to ((S)-2-hydroxy-pent-4-enyl)-carbamic acid
benzyl ester, which was converted to ((S)-2-hydroxy-4-oxo-butyl)-carbamic
acid benzyl ester in step B. This underwent a reductive amination
reaction with (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride in step C,
leading to
[(S)-2-hydroxy-4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-butyl]-carbanic
acid benzyl ester. Silylation in step D gave
[(S)-2-triethylsilanyloxy-4-((S)-4-triethylsilanyloxy-6-aza-spiro[2.5]oct-
-6-yl)-butyl]-carbamic acid benzyl ester, which was hydrogenated to
(S)-2-triethylsilanyloxy-4-((S)-4-triethylsilanyloxy-6-aza-spiro[2.5]oct--
6-yl)-butylamine in step E. This was converted to
(2,2-dimethoxy-ethyl)-[(S)-2-triethylsilanyloxy-4-((S)-4-triethylsilanylo-
xy-6-aza-spiro[2.5]oct-6-yl)-butyl]-amine in step F, followed by coupling
with (S)-2-(3,4-dichloro-phenylamino)-propionic acid (intermediate 24) in
step G, leading to
(S)-2-(3,4-dichloro-phenylamino)-N-(2,2-dimethoxy-ethyl)-N-[(S)-2-triethy-
lsilanyloxy-4-((S)-4-triethylsilanyloxy-6-aza-spiro[2.5]oct-6-yl)-butyl]-p-
ropionamide. Finally, reductive cyclization and concomitant desilylation
in step H afforded
(S)-4-(3,4-dichloro-phenyl)-1-[(S)-2-hydroxy-4-((S)-4-hydroxy-6-aza-spiro-
[2.5]oct-6-yl)-butyl]-3-methyl-piperazin-2-one. Colourless gum, MS: 456.3
(M+H).sup.+.

[0679]The title compound was produced in analogy with example 106, steps
A-G. Thus, esterification of
(S)-4-benzyloxycarbonylamino-2-hydroxy-butyric acid gave
(S)-4-benzyloxycarbonylamino-2-hydroxy-butyric acid ethyl ester, which
was reduced in step B, leading to ((S)-3,4-dihydroxy-butyl)-carbamic acid
benzyl ester. Hydrogenation in step C led to (S)-4-amino-butane-1,2-diol,
followed by reductive alkylation in step D, thus producing
(S)-4-(2,2-dimethoxy-ethylamino)-butane-1,2-diol. This was coupled with
2-(3,4-dichloro-phenylamino)-propionic acid (intermediate 11) to
2-(3,4-dichloro-phenylamino)-N-((S)-3,4-dihydroxy-butyl)-N-(2,2-dimethoxy-
-ethyl)-propionamide in step E, followed by reductive cyclization in step
F, leading to
4-(3,4-dichloro-phenyl)-1-((S)-3,4-dihydroxy-butyl)-3-methyl-piperazin-2--
one. Finally, mesylation and intramolecular cyclization, followed by
reaction with (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate
2) in step G afforded
4-(3,4-dichloro-phenyl)-1-[(S)-3-hydroxy-4-((S)-4-hydroxy-6-aza-spiro[2.5-
]oct-6-yl)-butyl]-3-methyl-piperazin-2-one. Light yellow foam, MS: 456.2
(M+H).sup.+.

Example A

[0680]Film coated tablets containing the following ingredients can be
manufactured in a conventional manner:

[0681]The active ingredient is sieved and mixed with microcrystalline
cellulose and the mixture is granulated with a solution of
polyvinylpyrrolidone in water. The granulate is mixed with sodium starch
glycolate and magesiumstearate and compressed to yield kernels of 120 or
350 mg respectively. The kernels are lacquered with an aqueous
solution/suspension of the above mentioned film coat.

Example B

[0682]Capsules containing the following ingredients can be manufactured in
a conventional manner:

[0685]The active ingredient is dissolved in a mixture of polyethylene
glycol 400 and water for injection (part). The pH is adjusted to 5.0 by
acetic acid. The volume is adjusted to 1.0 ml by addition of the residual
amount of water. The solution is filtered, filled into vials using an
appropriate overage and sterilized.

Example D

[0686]Soft gelatin capsules containing the following ingredients can be
manufactured in a conventional manner:

[0687]The active ingredient is dissolved in a warm melting of the other
ingredients and the mixture is filled into soft gelatin capsules of
appropriate size. The filled soft gelatin capsules are treated according
to the usual procedures.

Example E

[0688]Sachets containing the following ingredients can be manufactured in
a conventional manner:

[0689]The active ingredient is mixed with lactose, microcrystalline
cellulose and sodium carboxymethyl cellulose and granulated with a
mixture of polyvinylpyrrolidone in water. The granulate is mixed with
magnesium stearate and the flavouring additives and filled into sachets.

[0690]Unless stated to the contrary, all compounds in the examples were
prepared and characterized as described. All ranges recited herein
encompass all combinations and subcombinations included within that range
limit. All patents and publications cited herein are hereby incorporated
by reference in their entirety.